Psychoneuroimmunology Then and Now

See discussions, stats, and author profiles for this publication at: https://www.researchgate.
net/publication/51369196
Psychoneuroimmunology: Then and Now
Article in Behavioral and Cognitive Neuroscience Reviews · June 2004

DOI: 10.1177/1534582304269027 · Source: PubMed
CITATIONS READS
52 950
2 authors:
Monika Fleshner Mark L Laudenslager

University of Colorado Boulder University of Colorado
266 PUBLICATIONS 15,254 CITATIONS 231 PUBLICATIONS 5,301 CITATIONS
SEE PROFILE SEE PROFILE
Some of the authors of this publication are also working on these related projects:
Exercise, stress resistance and central serotonergic systems View project
All content following this page was uploaded by Mark L Laudenslager on 07 January 2014.
The user has requested enhancement of the downloaded file.

BEHAVIORAL
10.1177/1534582304269027
Fleshner, Laudenslager
AND COGNITIVE
/ PSYCHONEUROIMMUNOLOGY
NEUROSCIENCE REVIEWS
Psychoneuroimmunology:
Then and Now
Monika Fleshner
University of Colorado–Boulder
Mark L. Laudenslager
University of Colorado Health Sciences Center
Psychoneuroimmunology (PNI) emerged in the neurosciences in appeared in an article by Solomon and Moos (1964). In
the late 1970s to early 1980s and has extended to influence the that article, a potential role for personality factors and
fields of psychology, psychiatry, endocrinology, physiology, and emotions in autoimmune disease and schizophrenia was
the biomedical research community. This review documents the described. This article portended what was to become a
journey of PNI from the early 1980s to the present. Today, we rec- significant area of research in the neurosciences and psy-
ognize that the highly complex immune system interacts with an chosomatic medicine that was not to arrive until the early
equally complex nervous system in a bidirectional manner. 1980s. Psychoneuroimmunology (PNI) has grown dra-
Evolutionarily old signals continue to play a role in these com- matically in the past two decades. Ader, Felten, and
munications, as do mechanisms for protection of the host. The Cohen (1981) introduced the term psychoneuroimmunogy
disparity between physical and psychological stressors is only an as the title for their landmark book, which included
illusion. Host defense mechanisms respond in adaptive and reviews of the state of the art regarding the role of the
meaningful ways to both. The present review will describe a new central nervous system (CNS) in the complicated inter-
way of thinking about evolutionarily old molecules, heat shock play of behavior and the immune system. The term neuro
proteins, adding to a body of evidence suggesting that activation acknowledged the brain as a crucial component of this
of the acute stress response is a double-edged sword that can both system. Seven years later, the first issue of Brain, Behavior,
benefit and derail optimal immunity. and Immunity was published by the same group as editors.
The first issue covered topics ranging from conditioning
the immune response and stress effects on immune mea-
Key Words: psychoneuroimmunology, stress, immunity,
sures in animal models to stress, health, and immune
neuroendocrine regulation, sickness behavior, heat
relationships in humans. Brain, Behavior, and Immunity is
shock proteins, danger signal model
now the official journal of the PsychoNeuroImmunology
When the parts of the body and its humors are not in har- Research Society, which was chartered in 1993. Today, its
mony, then the mind is unbalanced and melancholy en- international membership exceeds 500. Obviously, PNI
sues, but on the other hand, a quiet and happy mind has moved in dramatic steps since the 1960s.
makes the whole body healthy.
—Ferenc (1680, as quoted in Solomon, 1993) Authors’ Note: Preparation of this article was supported in part by Na-
tional Institutes of Health research grants MH37373 (MLL), AI48555
The idea that mind and health are intertwined in a (MF), and MH068283 (MF). We wish to thank our collaborators over
bidirectional manner is certainly not a new concept, as the past 20 years for their encouragement and support of the projects
we have presented herein, particularly Steven Maier and Linda
indicated in the preceding quotation from the 17th cen- Watkins, who have contributed much to our understanding of the
tury. More than a century ago, an astute psychiatrist bidirectionality between the brain and the immune system. Finally, the
described a “rose cold” in a patient with an allergic disor- second author would like to acknowledge Harry J. Carlisle (1931-2003)
der to flowers (MacKenzie, 1896). MacKenzie (1896) for the example he set as a graduate mentor and scientist. Everyone will
noted that the patient responded with the same nasal certainly miss him.
stuffiness to a silk rose, presumably free of allergens, as to Behavioral and Cognitive Neuroscience Reviews
Volume 3 Number 2, June 2004 114-130
an actual rose. Forty years ago, an important conceptual- DOI: 10.1177/1534582304269027
ization regarding the interplay of mind and immunity © 2004 Sage Publications
114
Fleshner, Laudenslager / PSYCHONEUROIMMUNOLOGY 115
The majority of early research indicated that stressful THE 1980S: STRESS SUPPRESSES
experiences downregulated most measures of the im- THE IMMUNE RESPONSE
mune response, and it was assumed that this change was
the underpinning of poor health associated with stress- So what did we think we knew in the early 1980s? Ader
ors. PNI faced repeated grumblings regarding the ques- et al. (1981) brought together an extensive collection of
tion, Why should stress suppress the immune response articles from diverse researchers to review many aspects
in an adaptive system? Successful adaptation would pre- of PNI. This text seeded the soil for many important
dict that stressors should have a salubrious effect on the studies in PNI that followed. What we thought we knew
immune system if health and survival were key out- in the early to mid-1980s indicated that stress tended to
comes. An editorial in the New England Journal of Medicine suppress or downregulate many measures of immune
suggested that we might be placing too heavy a burden function that were used in research at that time. The pre-
on patients if they take responsibility for their improve- vailing thought was that stress suppressed immunity.
ment or decline based on emotional factors (Angell, Most of these approaches employed in vitro measures of
1985). These less than complimentary opinions were immunity. That is, specific immune components, lym-
made following an analysis of survival in patients with phocytes, were removed from the body by phlebotomy
cancers known to have poor prognosis and their associa- and placed into a variety of tissue culture systems. We will
tion with a lack of effect of psychosocial factors on their return to issues associated with this approach later.
outcome (Cassileth, Lusk, Miller, Brown, & Miller, Studies in rodents showed that simple stressors, such
1985). This seemed to be a clear case of throwing the as mild shock or restraint, had negative effects on the
baby out with the bath water. Because radiation, chemo- immune measures that were recognized at the time. The
therapy, and surgical approaches were not particularly physical stressors could be specified clearly and quantita-
effective for these patients, should we not also dismiss tively, for example, a lightly restrained rat received 100
these modalities as well? Of course not! Too high a set of five-second inescapable 1.6-mA foot shocks over a 100-
expectations was placed on early studies in PNI, and too minute test session (Feng et al., 1991; Fleshner, Bellgrau,
much responsibility was placed on the patients in their Watkins, Laudenslager, & Maier, 1995) or a mouse was
outcome when in point of fact, health is a combination restrained in a 50-ml conical centrifuge tube for 16
of many factors, not just our psyche alone. The biopsy- hours a day for 1, 4, 7, or 14 days (Feng et al., 1991). How-
chosocial model proposed by Engel (1977) indicated ever, there were psychological (e.g., nonphysical)
that health and wellness and their opposite, illness, are aspects of these stressors that contributed to the range of
the result of our genes, environment, experience, and variability in experimental results that was observed in
behavioral factors. these studies. These behavioral factors were typically not
PNI is here to stay, albeit as a slightly different itera- assessed. Indeed, Keller, Weiss, Schleifer, Miller, and
tion than that of the early years; PNI has proven its valid- Stein (1981) commented on the range of variance in the
ity. In this review, we will provide only a brief overview of home cage controls and apparatus controls compared to
PNI beginning in the 1980s to the present. We will focus the animals experiencing the stressor. Characteristics
in more detail on the potentially adaptive effects of such as dominance status in group-housed rodents
stressor exposure on the health of the organism and the (most often mice), nature of the weaning process by
role of a recently postulated stress signal, heat shock pro- commercial breeders, period of colony adaptation after
teins (Hsp; specifically, Hsp72), proteins that increase in shipping prior to testing, lighting cycle, and so on lead to
response to physical injury to tissue as well as psychologi- substantial differences in how subjects respond at base-
cal stressors. The early studies in PNI laid the ground- line (e.g., control conditions) or to acute stressors
work for the extraordinarily sophisticated work with applied in these studies (Maier & Laudenslager, 1988).
which we associate PNI today. Investigators are far more attentive to these factors today
The following review is not intended to be compre- than 20 years ago, and the quality of research in PNI, and
hensive as the growth of this field would make such a in immunology in general, has profited immeasurably.
review prohibitively long. Instead, we will attempt to hit A few exemplars of the preceding studies indicate
the high spots and use liberal reference to other reviews what was observed with regard to short-term stressors
for those who wish to delve further into this exciting and
and immune function in the decade of the 1980s. A com-
evolving field. We will conclude with a detailed overview
monly used measure at the time, lymphocyte activation
of a model suggesting Hsp may serve as important medi-
in response to mitogenic stimulation was suppressed fol-
ators between not only physical stressors but also psycho-
lowing exposure to stressors such as a mild tail shock
logical stressors and immune activation.
(Keller, Weiss, Schleifer, Miller, & Stein, 1983;
Laudenslager, Ryan, Drugan, Hyson, & Maier, 1983).
Although shock intensity, duration and frequency of
116 BEHAVIORAL AND COGNITIVE NEUROSCIENCE REVIEWS
exposure, and so forth were explored, the early studies appearance of specific antibodies to a highly immuno-
included detailed parametric investigations of the rela- genic foreign protein molecule, keyhole limpet hemo-
tionship between stressor exposure and immune modu- cyanin (KLH), in the blood during the development of
lation. Generally, higher intensity or longer duration was both the primary and secondary response to KLH follow-
more detrimental from the perspective of lymphocyte ing stressor exposure (Laudenslager et al., 1988). We
activation. Thus, as intensity of the shock was increased, found reliable results across a number of different con-
there was a greater suppression of the activation of lym- ditions (number of days of stressor exposure, time of day,
phocytes by mitogens (Keller et al., 1981). From these etc.) when the antibody response to antigenic challenge
investigations, it was generally concluded that “stress with KLH was measured using an enzyme-linked immun-
suppressed immunity” but based on a single measure of osorbent assay. Stressor exposure was uniformly associ-
immunity. Our group was no different, but we rapidly ated with lower specific antibody levels in the plasma of
came to recognize that host defense is the result of com- the participants. Recently, KLH has been used as a novel
plex interactions of many components acting in concert. challenge in studies that investigate the impact of stress,
Continued investigation by our group suggested that aging, and/or exercise in humans (T. P. Smith, Kennedy,
lymphocyte activation by mitogens was subject to far & Fleshner, 2004; A. Smith, Vollmer-Conna, et al., 2004).
more variability than we had initially expected (Maier & Early studies had indicated that psychological aspects
Laudenslager, 1988). such as behavioral control over the stressor (Lauden-
A concern at the time was with regard to the robust- slager et al., 1983) appeared to be important. For exam-
ness of the in vitro measure we were using, lymphocyte ple, lack of behavioral control over a stressor was suffi-
proliferation in response to mitogenic stimulation. At a cient to suppress lymphocyte activity associated with
meeting in 1987 in Lake Arrowhead, California, attended stressor exposure. Considerable variability was noted
by prominent investigators in PNI, Robert Ader made a across subjects, and this was not necessarily related to
poignant comment, “The immune response occurs in a a variable immune measure. Observing preexisting
neuroendocrine environment except that measured by behavioral characteristics or behavioral responses spe-
immunologists.” The in vitro measures, common in PNI cifically associated with the stressor were not registered
studies at that time, took place outside of the organism in most studies at that time. We later noted that specific
that had previously experienced the stressor. Lympho- antibody responses were attenuated in association with
cytes were removed from this environment, washed, and complex behavioral factors that did not necessarily
placed into a medium in which fetal calf serum was include a physically painful or harmful event.
added, eliminating the neurohumoral environment in Exposing young male rats to an aggressive intruder
which the stressor was experienced. Should one really rat (a retired breeder male) over several successive days
expect consistent reliable results that could be traced for brief periods of time was associated with suppression
back to the psychological impact of the stressor on regu- of the specific antibody response to KLH (Fleshner,
lation of the immune response in this artificially supple- Laudenslager, Simons, & Maier, 1989). This was not par-
mented environment? ticularly surprising and was expected. The remarkable
A paradigm shift from in vitro to in vivo approaches observation was that behaviors observed during the
for monitoring immune function in PNI research was interactions of the residents with the intruder were pre-
argued for by Maier and Laudenslager (1988). The in dictive of the magnitude of the resident’s specific anti-
vivo–specific antibody response to an antigenic chal- body response. That is, residents that showed a species-
lenge with a foreign protein represents many aspects of specific defeat posture (lying on their back exposing vul-
immune regulation beginning with the initial recogni- nerable surfaces or standing upright with ears pinned to
tion of not self (antigen), processing of the antigen by the head and forelimbs hanging limply in front) during
immune cells recognizing not self, regulation of this interactions with the intruder were far more likely to
response by intracellular communication molecules show suppressed specific antibody responses. Defeat
such as cytokines, production of the specific antibody behavior was not associated with wounding. In fact, the
toward the antigen, and finally binding of the antibody intruders were more likely to bite residents that fought
to the antigen typically resulting in removal or inactiva- back and did not display defeat behaviors. The presence
tion of the foreign protein or pathogen. Memory for the of defeat postures accounted for 40% of the variance
previous antigen can be easily tested by challenging with (reduction) in the specific antibody response in the resi-
the same antigen again. Assessment of the specific anti- dents exposed to intruders. Antibody responses of rats
body levels in the blood permits one to evaluate an end that fought back were similar to controls that had experi-
product of a finely orchestrated process. Based on a sug- enced handling and exposure to the intruder but with a
gestion from two immunologists, J. John Cohen and Plexiglas barrier between them that prevented direct
Nicholas Cohen (no relation), we elected to assess the social confrontation. Thus, variability in response to
stressor exposure (e.g., a territorial intruder) could be remained suppressed even in the presence of the opiate
accounted for by behavioral factors inherent to the blocker (Ben Eliyahu, Yirmiya, Shavit, & Liebeskind,
organism or their proclivity to adopt a defeat posture. 1990). Regulation of the immune response was indeed a
Although we did not determine the etiology of the complicated and multifactorial system. Adding a
response, it is very likely that the adoption of these behavioral component only increased the complexity of
behaviors is somehow related to their dominance status the relationships.
(Boccia, Laudenslager, Broussard, & Hijazi, 1992; More recently, studies using infectious viruses have
Laudenslager, Rasmussen, Berman, deBlois, & Suomi, identified significant differences between stressors, such
2000). Much of the stress literature has been dominated as restraint stress and the intruder model, with regard to
by studies that used experiences that, more often than resolution of damage to the lungs and antiviral resis-
not, have overwhelmed the stress response system. tance in general. Restraint stress was associated with
Observation of variability associated with subtle behav- attenuated lung damage and reduced mortality in mice
ioral influences is more likely to be revealed if the following inoculation with live virus (Sheridan et al.,
stressor is less severe or unique to the subject based on 1998). In contrast, when mice experienced social inter-
prior experience. actions with an intruder mouse, immune changes were
Another important in vivo approach to understand- quite different from restraint stress, and increased
ing immune regulation, host resistance, and stress was lethality of the virus followed a social stressor (Avitsur,
developed in the latter part of the 1980s. It involved pro- Stark, Dhabhar, & Sheridan, 2002; Avitsur, Stark, &
tection from an intravenously administered syngeneic Sheridan, 2001; Sheridan, 1998).
tumor cell (MADB106) in experimental animals (see Trafficking of lymphocytes between immune com-
Ben-Eliyahu & Page, 1992, for a detailed review). The partments is a well-known phenomenon to immunolo-
natural killer (NK) cell forms a first line of defense gists. However, PNI studies often obtained lymphocytes
toward virally infected cells and/or developing tumors for immune assays from a single immune compartment
(Whiteside & Herberman, 1989, 1995). Many studies (e.g., peripheral blood or spleen). Lymphocytes are not
indicated that in vitro measures of NK activity (cyto- a homogenous group of cells but include a number of
toxicity assays) were suppressed by acute stressors such as different cell types with very different properties
brief foot shock and that this was mediated in part via the (Coffman, Varkila, Scott, & Chatelain, 1991; Fowell,
endogenous opiate system (Shavit, Lewis, Terman, Gale, Mcknight, Powrie, Dyke, & Mason, 1991; Mosmann,
& Liebeskind, 1984). Importantly, these studies of 1991; Powrie & Coffman, 1993; Powrie & Mason, 1988).
impaired NK activity were paralleled by enhanced tumor Not surprisingly, results from different immune com-
proliferation in vivo after inoculation with an NK-sensi- partments revealed different effects based on the pres-
tive tumor cell line following stressor exposure (Ben- ence of different cellular characteristics. In human stud-
Eliyahu & Page, 1992). Thus, for these studies, the in ies, one is restricted to the most assessable immune
vitro measures (lysis of tumor cell lines in tissue culture) compartment, the peripheral blood. Patients are un-
were supported by a series of studies indicating that likely to consent to biopsies to obtain lymphocytes from
implanted tumor cell lines were similarly affected follow- lymph nodes or the spleen. Assay of cells from different
ing these stressors. compartments can be accomplished only in animal mod-
Although studies carried out in many different labo- els. These studies revealed different patterns of change
ratories suggested that shock experiences suppressed dependent on the site from which the sample was col-
lymphocyte proliferation (Keller, Schleifer, & Demetri- lected (Fleshner et al., 1992). In brief, cells collected
kopoulos, 1991; Laudenslager et al., 1983) and in vitro from specific immune compartments responsible for
NK activity (Shavit et al., 1983, 1984) in a similar manner, processing KLH (mesenteric lymph nodes and spleen)
interpretations that stress suppressed immunity were revealed changes in immune regulation (lower γ inter-
based on single measurements and represented an over- feron) that could account for reduced specific antibody
simplification. The simplicity of this interpretation levels (Fleshner, Hermann, et al., 1995). Consistent with
became clear when tandem studies of both NK activity these observations, social defeat in the rat was also
and lymphocyte responses to mitogens revealed that pat- observed to be associated with reduced γ interferon by
terns of change differed with regard to underlying specific types of lymphocytes (Stefanski, Solomon,
mechanisms controlling the changes (Cunnick, Lysle, Kling, Thomas, & Plaeger, 1996). As we moved from the
Armfield, & Rabin, 1988). An opioid blocker, naloxone, 1980s into the 1990s, researchers in PNI were develop-
reversed the effects on NK activity but failed to reverse ing sophisticated approaches to disentangling this com-
suppression of lymphocyte activation. However, chang- plicated system.
ing the stress paradigm from shock to a swim stress Studies in human populations paralleled the animal
resulted in naloxone insensitivity, and NK activity research, indicating, for the most part, that individuals
under stress had changes in immune regulation. The served signals used by the neuroendocrine system but
nature of the stressors ranged from the stress of care- produced by the immune cells. This was an extremely
giving for a disabled loved one to marital discord. Psychi- novel and important contribution to the growing under-
atric conditions, such as depression, frequently comor- standing of brain and immune relationships, and it con-
bid with these stressors were also the subject of focused tinues to influence research in this field.
studies. It appeared that there was a dose-response rela- The concept of bidirectional communication was
tionship between depression and the magnitude of im- introduced around the same time as the provocative
mune changes that were observed (Glaser et al., 1990; concept of “sickness behavior” (Hart, 1988). Hart (1988)
Irwin, Daniels, Bloom, Smith, & Weiner, 1987; Irwin, suggested that the symptoms we experience when we are
Lacher, & Caldwell, 1992; Kiecolt-Glaser, Dura, Speicher, ill (fever, fatigue, increased sleep, loss of appetite, inat-
Trask, & Glaser, 1991; Kiecolt-Glaser et al., 1987; tention to grooming, and/or depressed affect) are not
Schleifer, Keller, Camerino, Thornton, & Stein, 1983). pathological but rather part of an adaptive response. A
Uncontrollable naturally occurring stressors (earth- fever is central to this process in many illnesses. Fever is
quakes or hurricanes) were also associated with signifi- energy intensive, requiring considerable metabolic
cant modulation of the immune response, and individ- efforts to raise core temperature. Following exposure to
ual responses were modulated by behavioral differences an infectious or inflammatory agent, behavioral
inherent to the individuals (Benight et al., 1997; responses contribute to the elevation of body tempera-
Segerstrom, Solomon, Kemeny, & Fahey, 1998; Solo- ture in response to the elevation of the body tempera-
mon, Segerstrom, Grohr, Kemeny, & Fahey, 1997). It ture set point (Cabanac, Duclaux, & Gillet, 1970; Weiss,
became more widely accepted that stress was associated Laties, & Weiss, 1967). Furthermore, affective displea-
with modulation of the immune response and increased sure occurs in the presence of deviations of body temper-
the risk for clinical illness. An important set of observa- ature when the set point is elevated in febrile illnesses
tions made in the late 1980s would change the direction (Cabanac, 1971; Cabanac et al., 1970). These behavioral
of thought in PNI and the field of neuroscience in responses are phylogenetically old and are seen in ecto-
general. thermic species as well (which regulate body tempera-
ture via behavioral means to gain heat from the environ-
THE 1990S: THE DECADE OF ment; Kluger, 1979). Fever is an integral part of the host
“SICKNESS BEHAVIOR” response toward an infectious agent. When the fever is
blocked in laboratory animals, sublethal doses of infec-
The decade of the 1990s continued to provide grow- tious agents become lethal. The overlap of behavioral
ing evidence in support of links between brain and and immune response systems seems intuitive and criti-
immune function. By the end of the 1990s, the third edi- cal for optimal functioning in the prevention of serious
tion of Psychoneuroimmunology required two volumes to illness and clearing of infectious agents.
adequately cover the growing number of research con- The Blalock group noted that lymphocytes constitu-
tributions (Ader, Felten, & Cohen, 2001). Studies con- tively expressed and/or released a number of factors
ducted during this era confirmed direct links between that influenced hormonal regulation including
the brain and the immune system. Studies began to focus adrenocorticotropic hormone, the enkephalins and
on individual psychosocial differences and their contri- endorphins, thyroid stimulating hormone, growth hor-
butions to differences in outcome and the overall vari- mone and prolactin, vasoactive intestinal peptide, and
ance in PNI studies (Segerstrom, Kemeny, Lauden- many more (Blalock, 1994). Thus, stimulation with a
slager, 2001). This was an exciting and productive time viral pathogen stimulates lymphocytes to release
for PNI. But by far, one of the most significant contribu- cytokines, which stimulate the release of cortisol via a
tions of PNI to our understanding of behavior and neural pathway (Dunn & Vickers, 1994). Cytokines are
immune relationships was associated with the realization evolutionarily highly conserved regulatory molecules
that the interactions between the brain and immune that are released by immune cells and are responsible for
system were bidirectional. overall regulation of the immune response (Leite de
An important review article appeared in 1989 that was Moraes & Dy, 1997; Maggi, 1998; Mosmann, 1991; Peter-
titled “A Molecular Basis for Bidirectional Communica- son, Molitor, & Chao, 1998; Raber et al., 1998; Sher et al.,
tion Between the Immune and Neuroendocrine Sys- 1998; Wilson, Finch, & Cohen, 2002).
tems” by Ed Blalock. This review postulated that the Observations in animal models suggested that infec-
immune system could be viewed as a sensory organ that tious illness was associated with a number of distinct
detected pathogens and infectious agents in the internal behavioral properties that in many respects resemble
milieu and signaled their presence to the brain during properties of depression (Croonenberghs, Bosmans,
immune activation. The signaling occurred via con- Deboutte, Kenis, & Maes, 2002; Maes, 1997, 1999; Maes
et al., 1999). That is, when a person gets sick, the related 1997; Oka, Oka, & Hori, 2001). Other components of
feelings (fatigue, malaise, loss of interest in usual things, the acute phase response, such as a decrease in
social isolation, changes in appetite, and altered sleep) corticosteroid-binding globulin, are associated with
are associated with an increase in proinflammatory stressor exposure (Fleshner, Deak, et al., 1995). These
cytokines (interleukin [IL]-1, IL-6, and/or tumor necro- parallels between the APR and the stress response follow-
sis factor [TNF]; Dantzer, 2004; Goehler et al., 2000; ing a psychological stressor were pointed out by Maier
Maier, 2003; Maier & Watkins, 1998; Watkins & Maier, and colleagues (Deak, Nguyen, Fleshner, Watkins, &
1999; Watkins, Milligan, & Maier, 2001). Rats become Maier, 1999; Goehler et al., 2000; Maier, 2003; Maier,
hyperanalgesic, reduce motivated behaviors, decrease Nguyen, Deak, Milligan, & Watkins, 1999; Maier &
social interactions, and reduce activity following injec- Watkins, 1998; Watkins, Nguyen, Lee, & Maier, 1999).
tion of these inflammatory cytokines or the injection of The remaining portions of this review present in
substances that stimulate their release. Furthermore, the greater detail recent observations that suggest activation
action of cytokines has been shown to be on the CNS. of a stress response is not always detrimental to immu-
That is, centrally injected cytokines elicit these behaviors nity. In fact, it would seem unreasonable to propose that
at considerably lower doses, and their release has been the immunomodulatory effect of activation of a stress
demonstrated locally in the CNS. In summary, the paral- response would in all circumstances result in immuno-
lels between behaviors noted following a rise in these suppression. Such an interaction would not be advanta-
cytokines and a depressive episode are quite striking. geous to host survival and therefore would be less likely
The vagus nerve was identified as one of several routes to survive evolutionary selection. The following sections
through which cytokines might signal the brain that the describe recent findings that activation of the acute
immune system has been activated (Maier, Goehler, stress response is a double-edged sword that can both
Fleshner, & Watkins, 1998; Milligan et al., 1997; Watkins, benefit and derail optimal immunity. Specifically, we will
Goehler, et al., 1995; Watkins, Maier, & Goehler, 1995a, present a new way of thinking about evolutionarily old
1995b). The paraganglia of the vagus nerve possesses molecules, Hsp. Based on a recent series of studies, we
receptors specific for proinflammatory cytokines conclude that Hsp are released into the circulation after
(Goehler, et al., 1997), and thus a loop was closed that exposure to acute psychological and/or physical stress-
allowed the brain to be alerted to immune processes acti- ors and hypothesize that these proteins may function to
vated in the periphery. Rising levels of cytokines in the potentiate immune responses to bacterial or pathogenic
periphery associated with an inflammatory process challenge, facilitate host defense, and promote host
could signal the brain of the activation of the response. It survival during time of challenge.
has been further postulated that cytokines released
within the brain itself by accessory lymphoid cells and/ TODAY: STRESS AND
or glial cells could also activate neural structures (Maier, IMMUNOPOTENTIATION
2003; Watkins et al., 2001).
Another observation made during this period indi- As indicated previously, early PNI research focused
cated that acute stressors elicited physiological responses on the suppressive effects of stress on the immune
that closely paralleled inflammatory responses (Maier & response (Ader, Felten, & Cohen, 1991; Laudenslager &
Watkins, 1998; Maier, Watkins, & Fleshner, 1994). That Fleshner, 1994; Maier, Fleshner, & Watkins, 1998;
is, a short experience with a stressor was associated with a Padgett & Glaser 2003; Plotnikoff, Murgo, Faith, &
rise in plasma levels of proinflammatory cytokines and a Wybran, 1991). It later became clear that acute stressor
fever. It was as if the innate immune response had been exposure can enhance, as well as suppress, immune
activated. The immune response is often divided into response elements (Dhabhar 2000; Fleshner, Nguyen,
innate and adaptive responses (Belardelli & Ferrantini, Cotter, Watkins, & Maier, 1998). Interestingly, there is
2002). It is generally thought that the innate response some evidence that stress-induced stimulation of innate
represents a first line of defense against pathogens that immune responses (including the APR) may potentially
threaten the organism. The adaptive response then contribute to stress-induced suppression of aspects of
develops specific immunity to the pathogen(s). An ini- acquired or antigen-specific immunity (Fleshner,
tial response of the innate response is the acute phase Bellgrau, et al., 1995; Moraska et al., 2002) and hence the
reaction (APR; Baumann & Gauldrie, 1994). Briefly, the notion that the effects of stress on immunity is indeed a
APR is triggered by proinflammatory cytokines includ- double-edged sword. It is possible that stress-induced
ing IL-1, IL-6, and TNF-α. A crucial physiological stimulation of innate immunity under some specific cir-
response during the APR is a fever. Exposure to a brief cumstances could be in fact suppressive to acquired
stressor also evokes a febrile response in the rat immunity because of the highly cytotoxic and relatively
(Cabanac & Dardashti, 1999; Dantzer, 2004; Deak et al., nonspecific nature of innate immune responses. None-
theless, it is clear that many variables can affect the effect infection (Noursadeghi et al., 2002). This protection is
of stress on immune function; furthermore, exposure to due to enhanced early bacterial clearance, phagocytosis,
the same acute stressor can both stimulate innate and and neutrophil activation. At a cellular level, acute stressor
suppress acquired immune responses (Fleshner, exposure increases the neutrophil oxidative burst (J. A.
Bellgrau, et al., 1995, 1998; Moraska et al., 2002). Which Smith & Pyne, 1997) and phagocytic activity (Harmsen &
effect predominates depends on factors such as stressor Turney, 1985; Lyte, Nelson, & Thompson, 1990). In addi-
intensity and duration and the specific aspect of immu- tion, lipopolysaccharide-stimulated leukocyte nitric
nity measured (Campisi & Fleshner, 2003; Campisi, oxide (NO; Fleshner et al., 1998) and IL-1β (Moraska
Leem, & Fleshner, 2002; Deak et al., 1999; Fleshner, et al., 2002) responses are potentiated after acute
Bellgrau, 1995; Fleshner et al., 1998, 2002; Moraska stressor exposure. Similar effects on antigen-stimulated
et al., 2002). In general, chronic stressor exposure has NO production after exposure to a variety of acute stress-
been reported to impair both innate (Ben-Eliyahu, Page, ors have also been reported (Coussons-Read, Maslonek,
Yirmiya, & Shakhar, 1999; Ben-Eliyahu, Shakhar, Page, Fecho, Perez, & Lysle, 1994; Fecho, Maslonek, Coussons-
Stefanski, & Shakhar, 2000; Mercado, Quan, Padgett, Read, Dykstra, & Lysle, 1994; Lysle, Fecho, Maslonek, &
Sheridan, & Marucha, 2002; Padgett, Marucha, & D y k s tr a , 1 9 9 5 ). N e u tr o p h i l o x i d a ti v e b u r s t,
Sheridan, 1998; Rojas, Padgett, Sheridan, & Marucha, phagocytosis, NO production, TNF-α, and IL-1β produc-
2002) and acquired (Green-Johnson et al., 1996; tion play an important role in local inflammation (Ali,
Kusnecov et al., 1992; Moynihan, Ader, Grota, Haribabu, Richardson, & Snyderman, 1997; Bellingan,
Schachtman, & Cohen, 1990; Sheridan, Stark, Avitsur, & Caldwell, Howie, Dransfield, & Haslett, 1996; Dinarello,
Padgett, 2000; Zalcman & Anisman 1993) immunity. 2000; Ianaro, O’Donnell, Di Rosa, & Liew, 1994; Mac
Clearly, the impact that stressor exposure may have on Micking, Xie, & Nathan, 1997). Many of the cellular
immune function and host defense is complex. products secreted by activated macrophages/neutro-
In contrast to the earlier views of stress effects on phils are potent, nonspecific suppressors of pathogen
immune regulation and consistent with the work of growth (Zidel & Masek, 1998). For example, NO, prosta-
Dhabhar and colleagues (Dhabhar 1998, 2000, 2003), glandin (PGE2), and superoxide radicals are all toxic to
more recent evidence from Fleshner’s group suggests cells and function in a nonspecific fashion to kill patho-
that exposure to acute laboratory stressors facilitates gens (Tomioka & Saito, 1992). Are there any stress-
innate immune responses and thereby enhances host responsive signals that might lead to activation of the
defense against bacterial pathogens. immune system?
Innate Immunity Hsp72
As previously described, several aspects of innate im- Hsp consist of several families of highly conserved
munity are enhanced following exposure to an acute proteins that play a role in a number of important cellu-
stressor in a healthy organism. These components lar functions (Morimoto, 1994). Induction of intracell-
include the APR, neutrophil and macrophage cellular ular heat shock proteins (iHsp) by high temperatures
function, local in vivo inflammatory responses, and was first reported in 1962 by Ritossa, and the term heat
recovery from bacterial challenge. The APR is a constel- shock protein was first coined in 1974 (Tissieres, Mitchell,
lation of physiological changes initiated at a site of infec- & Tracy, 1974). Hsp affect multiple cellular processes
tion or trauma that facilitate the clearance of the patho- including limiting protein aggregation or clumping,
gen nonspecifically. Importantly, several components of facilitating protein refolding, and chaperoning or mov-
the APR are triggered by exposure to acute stress without ing proteins within the cell (Hartl, 1996; Morimoto,
exposure to a pathogen. For example, uncontrollable 1994), all of which function en masse to improve cell sur-
stressors in rodents increase levels of acute phase pro- vival in the face of a broad array of cellular stressors
teins such as haptoglobulin and α1-acid glycoprotein (Hartl, 1996; Morimoto, 1994).
(Deak et al., 1997). In addition, circulating IL-6 (Takaki, The Hsp70 family of proteins includes the constitu-
Huang, Somogyvari-Vigh, & Arimura, 1994), comple- tively expressed 73-kDa protein (HSC73) and a highly
ment function (Coe, Rosenberg, & Levine, 1988; stress-inducible 72-kDa protein (Hsp72; Hartl, 1996;
Fleshner et al., 2002), and circulating neutrophils Morimoto, 1994). Focusing on one intracellular mem-
(Fleshner et al., 2002) are increased following exposure ber of the 70-kDa Hsp family of proteins, iHsp72 is found
to acute stressors. Each of these substances facilitates the in nearly every cell of the body and can be upregulated
development and resolution of the local inflammatory after exposure to a variety of cellular and organismic
response (Baumann & Gauldie, 1994). These responses stressors (Hartl, 1996; Morimoto, 1994). Although basal
are adaptive because prior pharmacological stimulation concentrations of Hsp72 are low in most tissues, high
of the APR protects animals from lethal Escherichia coli concentrations of iHsp72 can be found in the absence of
stressors in some tissues including the frontal cortex of Nahas, Wood, & Pockley, 2000), hypertension (Pockley
the brain (Heneka et al., 2003), pituitary (Campisi, et al., 2002), and atherosclerosis (Pockley, Georgiades,
Leem, Greenwood, et al. 2003), adrenal (Campisi, Thuin, de Faire, & Frostegard, 2003) have chronically
Leem, Greenwood, et al., 2003), and brown fat (Matz, elevated plasma levels of eHsp72 relative to healthy
LaVoi, & Blake, 1996; Matz, LaVoi, Moen, & Blake, aged-matched controls. Indeed, Dybdahl et al. reported
1996). Induction of iHsp72 has been reported after in 2002 that patients with coronary artery disease have an
exposure to a variety of whole organism physical stress- acute increase in eHsp72 in response to coronary bypass
ors including heat or hyperthermia (Cvoro & Matic, surgery. Not long after these reports, our laboratory
2002; King, Lin, Lin, & Lee, 2002; Kregel & Moseley, (Campisi & Fleshner, 2003; Campisi, Leem, & Fleshner,
1996; Redaelli et al., 2001; Thomas et al., 2002), tail 2003; Fleshner, Campisi, & Johnson, 2003; Fleshner
shock (Campisi, Leem, Greenwood, et al., 2003), and et al., 2004) and others (Febbraio, Ott, et al., 2002; Walsh
restraint (Blake, Udelsman, Feulner, Norton, & et al., 2001) reported that in the absence of clinical dis-
Holbrook, 1991; Udelsman et al., 1993). Interestingly, ease states, rodents as well as humans rapidly increase
induction of iHsp72 is not restricted to physical stressors. the concentration of eHsp72 in their blood after expo-
Indeed, the experience of predatory fear (e.g., exposing sure to acute psychological and/or physical stressors.
rats to a cat) in the absence of direct contact is associated These articles were the first to demonstrate that an
with increases of iHsp72 in the brain without physical increase of eHsp72 in the blood occurs in healthy organ-
injury to the animal (Fleshner, Campisi, Amiri, & isms after exposure to acute stressors and led us to sug-
Diamond, 2004). gest that stress-induced eHsp72 release may be a previ-
One question that remains unanswered and is cur- ously unrecognized feature of the normal stress
rently a topic of intense investigation in the Fleshner lab- response. It is important to note that there are reports in
oratory is what specific factor (neurotransmitter or hor- the literature that in humans, eHsp60 (a 60-kDa form of
mone) released by stress is responsible for the induction Hsp) may also increase with chronic stress (Lewthwaite,
and/or release of Hsp72? Stress-associated signals Owen, Coates, Henderson, & Steptoe, 2002), bind to the
reported to increase iHsp72 concentrations include surface of macrophages (Habich, Baumgart, Kolb,
adrenocorticotropin hormone (Blake, Buckley, LaVoi, Burkart, 2002), and stimulate proinflammatory
& Bartlett, 1994; Blake et al., 1991), corticosterone cytokines (Kol, Lichtman, Finberg, Libby, & Kurt-Jones,
(Cvoro & Matic, 2002; Sun, Chang, Kirchhoff, & 2000). These responses lead to enhanced host defense
Knowlton, 2000; Valen et al., 2000), glycogen depriva- mechanisms. Indeed, there are growing numbers of
tion (Febbraio, Steensberg, et al., 2002; Santoro, 2000), indications that stress does not necessarily suppress the
and norepinephrine or epinephrine (Heneka et al., activity of the immune system and may in fact enhance its
2003; Maloyan & Horowitz, 2002; Matz, LaVoi, & Blake, activity. This is an important new line of thought in PNI.
1996; Matz, LaVoi, Moen, et al., 1996; Paroo & Noble,
1999; Udelsman, Blake, Stagg, & Holbrook, 1994; Generalizability
Udelsman, Li, Stagg, Gordon, & Kvetnansky, 1994). Is there something unique about the physical proper-
Note that these signals are all increased in response to ties of the stressor that damage the cells directly, thereby
either physical or psychological stressors. leading to a rise in Hsp? This is unlikely, as stress-induced
release of eHsp72 occurs following a variety of both
Extracellular Hsp
purely psychological and physical stressors. Fleshner’s
Although a great deal is already understood about group, in collaboration with Drs. Jerry Rudy and David
iHsp72, far less is known about the function of stress- Diamond, applied two approaches that activated a stress
induced extracellular Hsp72 (eHsp72). Appreciating response without physical injury: (a) exposure to a fear-
more about stress-induced eHsp72 is important because ful stimulus following fear conditioning and (b) a
it may contribute to stress influences on immune regula- predator stress paradigm.
tion and other effects. In fact, one normal physiological First, the conditioned contextual fear paradigm
function of endogenous eHsp72 may be to facilitate involves exposing rats to a series of mild but aversive foot
innate immune responses following acute pathogenic shocks delivered in a specific environment or context
challenge. In contrast, it is possible that during patho- (Barrientos, O’Reilly, & Rudy, 2002; Fleshner, Pugh,
physiological states, such as atherosclerosis or Alzhei- Tremblay, & Rudy, 1997; Pugh, Fleshner, Tremblay, &
mer’s disease, eHsp72 may exacerbate these chronic Rudy, 1997; Rudy 1993, 1994; Rudy & Morledge, 1994;
inflammatory processes. Rudy & O’Reilly 1999). The rats develop a conditioned
The presence of eHsp72 in the blood was only recently fear response to cues associated with that environment
observed. Individuals suffering from a variety of medical or context. Seven days following conditioning, a fear
problems including renal disease (Wright, Corton, El- response is initiated by simple reexposure to the same
context in the absence of shock. These animals show stress may function as a “messenger of stress” or “danger
freezing behavior when returned to the context. Prelimi- signal” for the immune system. Matzinger (1994, 1998;
nary data indicate that conditioned contextual fear Seong & Matzinger, 2004) first proposed the hypothesis
induces the release of eHsp72 into the blood after expo- that the body may release endogenous danger signals
sure to the context for 20 minutes, where shock had capable of stimulating immunity. In brief, the danger
been previously received. Thus, exposure to a psycholog- theory states that immune activation involves not only
ically fear-evoking situation is sufficient to stimulate self/nonself but also danger/nondanger, molecular rec-
eHsp72. ognition schemas. The danger theory postulates that
An example of an unlearned fear stimulus is reflected innate immune cells are activated by danger/alarm sig-
in the predatory-fear paradigm in which a subject is nals that are derived following damage to the cells.
exposed to a natural predator. Exposure of a rat to a cat Although the danger theory is controversial when
or cat fur stimulates a rise in corticosterone (Diamond, viewed as exclusionary, the ideas suggested are intrigu-
Park, Heman, & Rose, 1999; Mesches, Fleshner, Heman, ing when viewed as complementary to other models.
Rose, & Diamond, 1999; Park, Campbell, & Diamond, Innate immunity or the immune responses toward
2001). In collaboration with David Diamond (University antigens that are present without previous exposure to
of South Florida), Fleshner’s group showed in a convinc- that antigen has evolved several strategies for activation.
ing manner that rats released eHsp72 into circulation An important and unresolved question for the danger
following exposure to a cat (90 minutes with no physical theory is what molecules serve as danger signals to the
contact but with all the visual and olfactory stimuli pres- immune system? Our laboratory (Campisi & Fleshner,
ent; Fleshner et al., 2004). Fear-evocative stimuli trigger 2003; Fleshner et al., 2002, 2003) and others (Asea,
the acute stress response including the release of Kraeft, et al., 2000; Bethke et al., 2002; Breloer et al.,
eHsp72 in the absence of physical challenge. How does 2001; Chen, Syldath, Bellmann, Burkhart, & Kolb, 1999;
release of eHsp72 in response to psychological chal- Colaco, 1998; Habich et al., 2002; Moseley 1998; Ohashi,
lenges affect immune regulation? Burkart, Flohe, & Kolb, 2000; Todryk, Melcher,
Dalgleish, & Vile, 2000; Vabulas et al., 2002) have sug-
Immunostimulatory Effect of
gested that eHsp may serve this function. Today is an
Extracellular Hsp72
exciting time for this idea because Hsp fit the theoretical
The effect that Hsp72 has on the immune system is framework proposed by Matzinger, and there is cur-
context dependent, that is, influenced by its location. rently growing supporting experimental evidence. For
Induction of iHsp72 decreases cytokine production example, humans who experienced trauma had
whereas eHsp72 can robustly stimulate inflammatory increased serum levels of eHsp72, and higher levels of
cytokine production and other innate immune eHsp72 were correlated with improved survival (Pittet
responses (Asea, Kraeft, et al., 2000; Breloer et al., 2001; et al., 2002). Based on the danger theory, it would follow
Multhoff et al., 1999). Adding eHsp72 in vitro stimulates that if a danger signal serves to facilitate immune func-
inducible NO synthase (Panjwani, Popova, & Srivastava, tion and eHsp72 acts as a danger signal, then organisms
2002), NO (Campisi & Fleshner, 2003), TNF-α (Asea, with increased eHsp72 should have improved immune
Kraeft, et al., 2000; Campisi & Fleshner, 2003), IL-1 responses and facilitated host defense to some types of
(Asea, Kraeft, et al., 2000; Campisi & Fleshner, 2003), pathogenic challenges.
and IL-6 (Asea, Kraeft, et al., 2000; Campisi & Fleshner,
2003) production from macrophages and neutrophils. Innate Immune Cell Activation:
Furthermore, eHsp72 has been reported to stimulate Toll-Like Receptors Bind eHsp72
the human complement pathway (Prohaszka et al., 2002), The search for the eHsp72 receptor is a topic of
and these effects were proposed to be due to “naked” intense investigation and debate. There is evidence of a
Hsp72, that is, Hsp72 not bound to antigen (Asea, cell surface receptor for Hsp70 on macrophages and
Kabingu, Stevenson, & Calderwood, 2000; MacAry et al., neutrophils (Asea et al., 2002; Asea, Kabingu, et al., 2000;
2004). This has recently led to the controversial sugges- Reed & Nicchitta, 2000; Sondermann, Becker, Mayhew,
tion (Gao & Tsan, 2003a, 2003b) that Hsp72 is Wieland, & Hartl, 2000), B cells (Arnold-Schild et al.,
immunostimulatory in its own right and not simply act- 1999), and NK cells (Gross, Hansch, Gastpar, &
ing as an adjuvant or response booster (Asea, Kabingu, Multhoff, 2003; Multhoff et al., 2001). Cell-surface bind-
et al., 2000; MacAry et al., 2004; Srivastava, 2002). ing proteins or receptors for eHsp have been noted.
Most research to date, however, suggests that eHsp72
Hsp72 and the Danger Theory
transduces an inflammatory signal to innate immune
Release of eHsp72 during times of stress can stimulate cells (macrophages, dendritic cells, and neutrophils) by
innate immunity. Furthermore, eHsp72 released during binding to toll-like receptor-2 (TLR2) and/or TLR4 in a
CD14 dependent fashion (Asea et al., 2002; Asea, Kraeft, be an important mediator; however, the mechanisms
et al., 2000; Vabulas et al., 2002; Visintin et al., 2001). involved in stress-induced facilitation of NO and recov-
Mammalian toll-like receptors are transmembrane pro- ery from bacterial inflammation remain unknown.
teins that are evolutionarily conserved from very primi-
tive organisms (such as insects) to humans (Akira, Stress Facilitates Recovery From
Takeda, Kaisho, 2001). It has been suggested that just as Subcutaneous E. coli Challenge:
released eHsps may function as “danger signals” or “mes- A Role for eHsp72
sengers of stress” to the immune system, and the TLRs Our laboratory has completed a series of studies that
may function as surveillance receptors for those signals support the hypothesis that stress-induced increases in
(G. B. Johnson, Brunn, Tang, & Platt, 2003). In addition, eHsp72 function to facilitate innate immunity in the
exposure to prior injury stress was recently reported to presence of pathogenic challenge (E. coli). First, rats
produce a long-term (1-7 days) potentiation of TLR2 exposed to tail shock stress and challenged with subcuta-
and TLR4-induced IL-1α, IL-6, and TNF-α production neous E. coli have an increase in eHsp72 at the site of
by spleen cells (Paterson et al., 2003), and chronic social inflammation (Campisi, Leem, & Fleshner, 2003). Sec-
stress (Avitsur et al., 2003) modulates TLR4-mediated ond, eHsp72 administered to the site of inflammation in
responses. These data support the hypothesis that stress- the absence of stress improved recovery from bacterial
induced modulation of innate immune function may challenge (Campisi, Leem, & Fleshner, 2003). Third, in
involve TLR2 and TLR4. collaboration with Dr. Alexzander Asea (Boston Univer-
sity School of Medicine), in vivo immunoneutralization
Stress Facilitates Recovery From
of eHsp72 (anti-Hsp70-Ab46) at the site of inflammation
Subcutaneous Bacterial Challenge:
attenuated the facilitatory effect of tail shock stress on
A Role for NO
bacterial inflammation development and resolution
Using subcutaneous bacteria (E. coli), the Fleshner (unpublished observations).
group tested whether exposure to acute tail shock prior Figure 1 depicts the model proposed by Fleshner and
to bacterial challenge would improve host defense due colleagues that stress-induced release of eHsp72 acts in
to potentiation of innate immunity (Campisi et al., 2002; concert with other aspects of the APR (neutrophilia,
Campisi & Fleshner, 2003; Campisi, Leem, & Fleshner, NO/O2–, complement activation, etc.) to facilitate host
2003). Rats exposed to tail shock stress and subcutane- defense (Campisi, Leem, & Fleshner, 2003; Fleshner
ously injected with 2.5 × 109 colony forming units (CFU) et al., 2003). Specifically, it is proposed that exposure to
of freshly grown E. coli immediately after stressor termi- acute stress can release eHsp72 into the circulation. Fol-
nation resolve their inflammation 10 to 14 days faster lowing challenge with bacterial or other pathogenic sub-
(Campisi et al., 2002; Campisi & Fleshner, 2003; stance, eHsp72 may extravasate from the blood into the
Campisi, Leem, & Fleshner, 2003), experience less subcutaneous space due to bacterial-stimulated release
bacterial-induced body weight loss (Campisi et al., of other inflammatory mediators that render the blood
2002), and release 300% more NO at the inflammatory vessel leaky (PGE2, BK, etc.; Ali et al., 1997). The accu-
site when compared to bacterially injected nonstressed mulation of eHsp72 at the inflammatory site binds to
controls (Campisi, Leem, & Fleshner, 2003). It has been TLR2 and TLR4 on macrophage and/or neutrophils.
demonstrated that stress-induced potentiation of NO is Macrophages and/or neutrophils stimulated in this
important in host defense against bacteria because inhi- manner mount potentiated innate immune responses
bition of NO at the inflammatory site with L-NIO (NOS (i.e., NO, TNF-α, IL-1, IL-6) that result in enhanced bac-
inhibitor) reduces the effects of stress on facilitating terial killing. The release of eHsp72 in response to a
recovery from bacterial challenge (Campisi, Leem, & global stressor such as uncontrollable tail shock, there-
Fleshner, 2003). NO affects almost every stage of inflam- fore, facilitates innate immune function only in the pres-
mation including leukocyte migration, adherence, anti- ence of pathogenic challenge. This is consistent with
microbial activities, and phagocytic ability is important. previous data on the priming effects of stress on innate
In fact, NO also acts to restrict the development of immunity (J. D. Johnson, O’Connor, Deak, Spencer,
inflammation (Ali et al., 1997). One beneficial effect of et al., 2002; J. D. Johnson, O’Connor, Deak, Stark, et al.,
stress on recovery from bacterial challenge could be 2002; J. D. Johnson, O’Connor, Hansen, Watkins, &
greater NO-mediated bacterial killing. Consistent with Maier, 2002).
this idea is that rats challenged with E. coli after stress
have fewer E. coli CFU retrieved from the inflammatory THE FUTURE
site 2, 4, and 6 hours after challenge compared to non-
stressed E. coli challenged controls (Campisi, Leem, & What we had learned from early physiological experi-
Fleshner, 2003). The enhanced release of NO appears to ments was that stress, particularly when intense or pro-
E.coli
E.coli NO NO E.coli
NO E.coli
Hsp72
Hsp72
Macrophage N
Subcutaneous
Hsp72 Hsp72 Space
Hsp72
N
Hsp72
Hsp72
N N N Blood Vessel
N = Neutrophil = CD14
= LPS = TLR2/4
= Hsp72 NO = Nitric Oxide
Figure 1: Stress-Induced Release of eHsp72 Acts in Concert With Other Aspects of the Acute Phase Response (Neutrophilia, NO/O2–, Comple-
ment Activation, etc.) to Facilitate Host Defense.
NOTE: Exposure to acute stress can release eHsp72 into the circulation. If the animals or people are challenged with bacterial or other pathogenic
substance, eHsp72 may extravasate from the blood into the subcutaneous space due to pathogenic-stimulated release of other inflammatory media-
tors that render the blood vessel leaky (PGE2, BK, etc.). Extracellular Hsp72 accumulates at the inflammatory site and binds to TLR2 and TLR4 on
macrophage and/or neutrophils. Macrophages and/or neutrophils that have received a stimulatory signal via CD14 binding to LPS will mount po-
tentiated innate immune responses (i.e., NO, TNF-α, IL-1, IL-6) that result in optimal bacterial/pathogenic killing. The release of eHsp72 in re-
sponse to a global stressor such as uncontrollable tail shock, therefore, facilitates innate immune function only in the presence of pathogenic
challenge.
longed, appeared detrimental to the health of the organ-

ism. Early studies using cold or heat stress indicated that applied in developing this conceptual model were quite
after time, the organism adapted, but under more pro- extreme and would not be approved by today’s Institu-
longed or extreme conditions, thermal extremes led to tional Animal Care and Use Committees. Although heu-
death. From these early observations, Hans Selye (1946) ristically valuable, we now know this model was an over-
described the General Adaptation Syndrome in which simplification. A number of investigators have expanded
the response to a stressor was initially associated with a the implications of this model to include factors that
suppressed adaptive response (alarm reaction) that sub- were not previously considered such as socioeconomic
sequently recovered (period of adaptation) to provide status, chronicity of the stressor, or the chronological age
increased resistance but that could eventually fail if the of the individual (McEwen, 1998, 2000; McEwen & Stel-
stressor persisted or was intense (stage of exhaustion). It lar, 1993). An important question arises regarding the
is to Selye’s credit that he indicated that psychological wide range of variability in the responses to what might
factors could also activate this system. Similar responses ostensibly be the same stressor. Selye’s (1946) model
of Hsp to either physical or psychological stressors cor- would lead one to expect common responses across indi-
roborates Selye’s conceptualization. viduals and, to some extent, stressors. Recall that the
Selye’s (1946) model further suggested that the stressors applied in early animal studies were generally
nature of the adaptive response leading to resistance was quite extreme. It is very likely that by their very nature,
generally similar across stressors. If we put the General these stressors may have pushed the ability of the organ-
Adaptation Syndrome in context, many of the stressors ism to adapt or respond to these stressors to their limit.
Smaller, more subtle effects of psychological stressors Asea, A., Kabingu, E., Stevenson, M. A., & Calderwood, S. K. (2000).
HSP70 peptide-bearing and peptide-negative preparations act as
were not generally considered by the General Adapta- chaperokines. Cell Stress and Chaperones, 5, 425-431.
tion Syndrome. Individual differences in response to Asea, A., Kraeft, S. K., Kurt-Jones, E. A., Stevenson, M. A., Chen, L. B.,
common stressors have become a central focus in many Finberg, R. W., et al. (2000). HSP70 stimulates cytokine produc-
tion through a CD14-dependant pathway, demonstrating its dual
studies of behavior-immune-health relationships (see a role as a chaperone and cytokine. Nature Medicine, 6, 435-442.
special issue of Brain, Behavior, and Immunity on the topic Asea, A., Rehli, M., Kabingu, E., Boch, J. A., Bare, O., Auron, P. E., et
of individual differences; Kemeny & Laudenslager, al. (2002). Novel signal transduction pathway utilized by
extracellular HSP70: Role of toll-like receptor (TLR) 2 and TLR4.
1999). Stability of these differences has also become Journal of Biological Chemistry, 277, 15028-15034.
important in providing credibility to their role in the Avitsur, R., Padgett, D. A., Dhabhar, F. S., Stark, J. L., Kramer, K. A.,
variance noted in behavior-immune relationships in Engler, H., et al. (2003). Expression of glucocorticoid resistance
following social stress requires a second signal. Journal of Leukocyte
large populations (Cohen, Doyle, Turner, Alper, & Biology, 74, 507-513.
Skoner, 2003; Cohen, Miller, & Rabin, 2001). The Avitsur, R., Stark, J. L., Dhabhar, F. S., & Sheridan, J. F. (2002). Social
sources of these individual differences may be genetic, stress alters splenocyte phenotype and function. Journal of
Neuroimmunology, 132, 66-71.
developmental, experiential, and/or stressor depend- Avitsur, R., Stark, J. L., & Sheridan, J. F. (2001). Social stress induces
ent. Thus, defining simple relationships between behav- glucocorticoid resistance in subordinate animals. Hormones &
ior (e.g., brain) and immunity is not likely to be forth- Behavior, 39, 247-257.
Barrientos, R. M., O’Reilly, R. C., & Rudy, J. W. (2002). Memory for
coming. Differences in conceptualization of behavioral context is impaired by injecting anisomycin into dorsal hippocam-
and physiological organization, of which there are many, pus following context exploration. Behavioral Brain Research, 134,
are likely to lead to diverse expectations regarding pre- 299-306.
dictions. The immune system is a multicomponent, Baumann, H., & Gauldie, J. (1994). The acute phase response. Immu-
nology Today, 15, 74-80.
highly regulated system. Its operating characteristics will Belardelli, F., & Ferrantini, M. (2002). Cytokines as a link between
not be captured by single functional measures, a fact that innate and adaptive antitumor immunity. Trends in Immunology,
PNI came to recognize many years ago and as indicated 23, 201-208.
Bellingan, G. J., Caldwell, H., Howie, S. E., Dransfield, I., & Haslett, C.
by observation regarding Hsp. (1996). In vivo fate of the inflammatory macrophage during the
It is now clear that the function of Hsp72 depends on resolution of inflammation: Inflammatory macrophages do not
its localization: intracellular versus extracellular. A great die locally, but emigrate to the draining lymph nodes. Journal of
Immunology, 157, 2577-2585.
deal is known about the intracellular functions of stress- Ben-Eliyahu, S., & Page, G. G. (1992). In vivo assessment of natural
induced Hsp72. However, relatively little is understood killer cell activity in rats. Progress in Neuroendocrinimmunology, 5,
about its extracellular functions. Previous work has led 199-214.
Ben-Eliyahu, S., Page, G. G., Yirmiya, R., & Shakhar, G. (1999). Evi-
to the proposal that eHsp72 is an endogenous stress mol- dence that stress and surgical interventions promote tumor devel-
ecule that functions to facilitate innate immunity opment by suppressing natural killer cell activity. International
(Campisi, Leem, & Fleshner, 2003; Fleshner et al., 2003). Journal of Cancer, 80, 880-888.
Ben-Eliyahu, S., Shakhar, G., Page, G. G., Stefanski, V., & Shakhar, K.
Clearly, eHsp72 can play a positive and/or adaptive role (2000). Suppression of NK cell activity and of resistance to metas-
in normal stress physiology. One future implication of tasis by stress: A role for adrenal catecholamines and beta-
these results is that eHsp72 may also play a negative role adrenoceptors. Neuroimmunomodulation, 8, 154-164.
Ben Eliyahu, S., Yirmiya, R., Shavit, Y., & Liebeskind, J. C. (1990).
in pathological states, such that exposure to stress and Stress-induced suppression of natural killer cell cytotoxicity in the
the release of eHsp72 could also exacerbate inflamma- rat: A naltrexone-insensitive paradigm. Behavioral Neuroscience,
tory disease states. There is much to keep us busy for 104, 235-238.
Benight, C. C., Antoni, M. H., Kilbourn, K., Ironson, G., Kumar, M. A.,
another 25 years. Fletcher, M. A., et al. (1997). Coping self-efficacy buffers psycho-
logical and physiological disturbances in HIV-infected men fol-
REFERENCES lowing a natural disaster. Health Psychology, 16, 248-255.
Ader, R., Felten, D. L., & Cohen, N. (1981). Psychoneuroimmunology. Bethke, K., Staib, F., Distler, M., Schmitt, U., Jonuleit, H., Enk, A. H.,
New York: Academic Press. et al. (2002). Different efficiency of heat shock proteins (HSP) to
Ader, R., Felten, D. L., & Cohen, N. (1991). Psychoneuroimmunology activate human monocytes and dendritic cells: Superiority of
(2nd ed.). New York: Academic Press. HSP60. Journal of Immunology, 169, 6141-6148.
Ader, R., Felten, D. L., & Cohen, N. (2001). Psychoneuroimmunology Blake, M. J., Buckley, A. R., LaVoi, K. P., & Bartlett, T. (1994). Neural
(3rd ed.). New York: Academic Press. and endocrine mechanisms of cocaine-induced 70k-Da heat
Akira, S., Takeda, K., & Kaisho, T. (2001). Toll-like receptors: Critical shock protein expression in aorta and adrenal gland. Journal of
proteins linking innate and acquired immunity. Nature Immunol- Pharmacological Experimental Therapy, 268, 522-529.
ogy, 2, 675-680. Blake, M. J., Udelsman, R., Feulner, G. J., Norton, D. D., & Holbrook,
Ali, H., Haribabu, B., Richardson, R. M., & Snyderman, R. (1997). N. J. (1991). Stress-induced heat shock protein 70 expression in
Mechanisms of inflammation and leukocyte activation. Medical adrenal cortex: An adrenocorticotropic hormone-sensitive, age-
Clinics of North America, 81, 1-28. dependent response. Proceedings of the National Academy of Science of
Angell, M. (1985). Disease as a reflection of the psyche. New England the United States of America, 88, 9873-9877.
Journal of Medicine, 312, 1570-1572. Blalock, J. E. (1989). A molecular basis for bidirectional communica-
Arnold-Schild, D., Hanau, D., Spehner, D., Schmid, C., Rammensee, tion between the immune and neuroendocrine systems. Physiologi-
H. G., de la Salle, H., et al. (1999). Cutting edge: Receptor- cal Reviews, 69, 1-32.
mediated endocytosis of heat shock proteins by professional Blalock, J. E. (1994). The syntax of immune-neuroendocrine commu-
antigen-presenting cells. Journal of Immunology, 162, 3757-3760. nication. Immunology Today, 15, 504-511.
Boccia, M. L., Laudenslager, M. L., Broussard, C. L., & Hijazi, A. S. Deak, T., Nguyen, K. T., Fleshner, M., Watkins, L. R., & Maier, S. F.
(1992). Immune responses following competitive dominance (1999). Acute stress may facilitate recovery from a subcutaneous
water tests in two species of macaques. Brain, Behavior, and Immu- bacterial challenge. Neuroimmunomodulation, 6, 344-354.
nity, 6, 201-213. Dhabhar, F. S. (1998). Stress-induced enhancement of cell-mediated
Breloer, M., Dorner, B., More, S. H., Roderian, T., Fleischer, B., & von immunity. Annals of the New York Academy of Science, 840, 359-372.
Bonin, A. (2001). Heat shock proteins as “danger signals”: Dhabhar, F. S. (2000). Acute stress enhances while chronic stress sup-
Eukaryotic Hsp60 enhances and accelerates antigen-specific IFN- presses skin immunity: The role of stress hormones and leukocyte
gamma production in T cells. European Journal of Immunology, 31, trafficking. Annals of the New York Academy of Science, 917, 876-893.
2051-2059. Dhabhar, F. S. (2003). Stress, leukocyte trafficking, and the augmen-
Cabanac, M. (1971). Physiological role of pleasure. Science, 173, 1103- tation of skin immune function. Annals of the New York Academy of
1107. Science, 992, 205-217.
Cabanac, M., & Dardashti, M. (1999). Emotional fever in rats persists Diamond, D. M., Park, C. R., Heman, K. L., & Rose, G. M. (1999).
after vagotomy. Physiology & Behavior, 67, 347-350. Exposing rats to a predator impairs spatial working memory in the
Cabanac, M., Duclaux, R., & Gillet, A. (1970). Behavioral thermo- radial arm water maze. Hippocampus, 9, 542-552.
regulation in the dog: Effects of fever and thyroxine. [in French]. Dinarello, C. A. (2000). Proinflammatory cytokines. Chest, 118, 503-
Physiology & Behavior, 5, 697-704. 508.
Campisi, J., & Fleshner, M. (2003). The role of extracellular Hsp72 in Dunn, A. J., & Vickers, S. L. (1994). Neurochemical and neuro-
acute stress-induced potentiation of innate immunity in physically endocrine responses to Newcastle disease virus administration in
active rats. Journal of Applied Physiology, 94, 43-52. mice. Brain Research, 645, 103-112.
Campisi, J., Leem, T. H., & Fleshner, M. (2002). Acute stress decreases Dybdahl, B., Wahba, A., Lien, E., Flo, T. H., Waage, A., Qureshi, N.,
inflammation at the site of infection: A role for nitric oxide. Physi- et al. (2002). Inflammatory response after open heart surgery:
ology & Behavior, 77, 291-299. Release of heat-shock protein 70 and signaling through toll-like
Campisi, J., Leem, T. H., & Fleshner, M. (2003). Stress-induced receptor-4. Circulation, 105, 685-690.
extracellular HSP72 is a functionally significant danger signal to Engel, G. L. (1977). The need for a new medical model: A challenge
the immune system. Cell, Stress and Chaperones, 8, 272-286. for biomedicine. Science, 196, 129-136.
Campisi, J., Leem, T. H., Greenwood, B. N., Hansen, M. K., Moraska, Febbraio, M. A., Ott, P., Nielsen, H. B., Steensberg, A., Keller, C.,
A., Higgins, K., et al. (2003). Habitual physical activity facilitates Krustrup, P., et al. (2002). Exercise induces hepatosplanchnic
stress-induced HSP72 induction in brain, peripheral and immune release of heat shock protein 72 in humans. Journal of Physiology,
tissues. American Journal of Physiology, 284, 520-530. 544, 957-962.
Cassileth, B. R., Lusk, E. J., Miller, D. S., Brown, L. L., & Miller, C. Febbraio, M. A., Steensberg, A., Walsh, R., Koukoulas, I., van Hall, G.,
Saltin, B., et al. (2002). Reduced glycogen availability is associated
(1985). Psychosocial correlates of survival in advanced malignant
with an elevation in HSP72 in contracting human skeletal muscle.
disease? New England Journal of Medicine, 312, 1551-1555.
Journal of Physiology, 538, 911-917.
Chen, W., Syldath, U., Bellmann, K., Burkart, V., & Kolb, H. (1999).
Fecho, K., Maslonek, K. A., Coussons-Read, M. E., Dykstra, L. A., &
Human 60-kDa heat-shock protein: A danger signal to the innate
Lysle, D. T. (1994). Macrophage-derived nitric oxide is involved in
immune system. Journal of Immunology, 162, 3212-3219.
the depressed concanavalin A responsiveness of splenic lympho-
Coe, C. L., Rosenberg, L. T., & Levine, S. (1988). Effect of maternal
cytes from rats administered morphine in vivo. Journal of Immunol-
separation on the complement system and antibody responses in
ogy, 152, 5845-5852.
infant primates. International Journal of Neuroscience, 40, 289-302.
Feng, N., Pagniano, R., Tovar, C. A., Bonneau, R. H., Glaser, R., &
Coffman, R. L., Varkila, K., Scott, P., & Chatelain, R. (1991). Role of
Sheridan, J. F. (1991). The effect of restraint stress on the kinetics,
cytokines in the differentiation of CD4+ T-cell subsets invivo.
magnitude, and isotype of the humoral immune response to influ-
Immunology Reviews, 123, 189-207. enza virus infection. Brain, Behavior, and Immunity, 5, 370-382.
Cohen, S., Doyle, W. J., Turner, R. B., Alper, C. M., & Skoner, D. P. Fleshner, M., Bellgrau, D., Watkins, L. R., Laudenslager, M. L., &
(2003). Emotional style and susceptibility to the common cold. Maier, S. F. (1995). Stress-induced changes in the mixed lympho-
Psychosomatic Medicine, 65, 652-657. cyte reaction is dependent on macrophages but not on shifts in
Cohen, S., Miller, G. E., & Rabin, B. S. (2001). Psychological stress and phenotypes. Journal of Neuroimmunology, 56, 45-52.
antibody response to immunization: a critical review of the human Fleshner, M., Campisi, J., Amiri, L., & Diamond, D. M. (2004). Cat
literature. Psychosomatic Medicine, 63, 7-18. exposure induces both intra- & extra-cellular HSP72: The role of
Colaco, C. A. (1998). Towards a unified theory of immunity: Den- adrenal hormones. Psychoneuroendocrinology, 29, 1142-1152
dritic cells, stress proteins and antigen capture. Cellular and Molec- Fleshner, M., Campisi, J., Deak, T., Greenwood, B. N., Kintzel, J. A.,
ular Biology, 44, 883-890. Leem, T. H., et al. (2002). Acute stressor exposure facilitates
Coussons-Read, M. E., Maslonek, K. A., Fecho, K., Perez, L., & Lysle, innate immunity more in physically active than in sedentary rats.
D. T. (1994). Evidence for the involvement of macrophage- American Journal of Physiology, 282, R1680-1686.
derived nitric oxide in the modulation of immune status by a con- Fleshner, M., Campisi, J., & Johnson, J. D. (2003). Can exercise stress
ditioned aversive stimulus. Journal of Neuroimmunololgy, 50, 51-58. facilitate innate immunity? A functional role for stress-induced
Croonenberghs, J., Bosmans, E., Deboutte, D., Kenis, G., & Maes, M. extracellular Hsp72. Exercise Immunology Reviews, 9, 6-24.
(2002). Activation of the inflammatory response system in autism. Fleshner, M., Deak, T., Spencer, R. L., Laudenslager, M. L., Watkins,
Neuropsychobiology, 45, 1-6. L. R., Maier S. F. (1995). A long-term increase in basal levels of
Cunnick, J. E., Lysle, D. T., Armfield, A., & Rabin, B. S. (1988). Shock- corticosterone and a decrease in corticosteroid-binding globulin
induced modulation of lymphocyte responsiveness and natural after acute stressor exposure. Endocrinology, 136, 5336-5342.
killer activity: Differential mechanisms of induction. Brain, Behav- Fleshner, M., Hermann, J., Lockwood, L. L., Laudenslager, M. L.,
ior, and Immunity, 2, 102-113. Watkins, L. R., & Maier, S. F. (1995). Stressed rats fail to expand
Cvoro, A., & Matic, G. (2002). Hyperthermic stress stimulates the the CD45RC+CD4+ (Th1-like) T cell subset in response to KLH:
association of both constitutive and inducible isoforms of 70 kDa Possible involvement of IFN-gamma. Brain, Behavior, & Immunity,
heat shock protein with rat liver glucocorticoid receptor. Interna- 9, 101-112.
tional Journal of Biochemistry and Cell Biology, 34, 279-285. Fleshner, M., Laudenslager, M. L., Simons, L., & Maier, S. F. (1989).
Dantzer, R. (2004). Innate immunity at the forefront of psychoneuro- Reduced serum antibodies associated with social defeat in rats.
immunology. Brain, Behavior, and Immunity, 18, 1-6. Physiology & Behavior, 45, 1183-1187.
Deak, T., Meriwether, J. L., Fleshner, M., Spencer, R. L., Abouhamze, Fleshner, M., Nguyen, K. T., Cotter, C. S., Watkins, L. R., & Maier, S. F.
A., Moldawer, L. L., et al. (1997). Evidence that brief stress may (1998). Acute stressor exposure both suppresses acquired immu-
induce the acute phase response in rats. American Journal of Physiol- nity and potentiates innate immunity. American Journal of Physiol-
ogy, 273, R1998-2004. ogy, 275, R870-878.
Fleshner, M., Pugh, C. R., Tremblay, D., & Rudy, J. W. (1997). DHEA-S Johnson, J. D., O’Connor, K. A., Deak, T., Spencer, R. L., Watkins,
selectively impairs contextual-fear conditioning: Support for the L. R., & Maier, S. F. (2002). Prior stressor exposure primes the
antiglucocorticoid hypothesis. Behavioral Neuroscience, 111, 512- HPA axis. Psychoneuroendocrinology, 27, 353-365.
517. Johnson, J. D., O’Connor, K. A., Deak, T., Stark, M., Watkins, L. R., &
Fleshner, M., Watkins, L. R., Lockwood, L. L., Bellgrau, D., Maier, S. F. (2002). Prior stressor exposure sensitizes LPS-induced
Laudenslager, M. L., & Maier, S. F. (1992). Specific changes in lym- cytokine production. Brain, Behavior, and Immunity, 16, 461-476.
phocyte subpopulations: A potential mechanism for stress- Johnson, J. D., O’Connor, K. A., Hansen, M. K., Watkins, L. R., &
induced immunomodulation. Journal of Neuroimmunology, 41, 131- Maier, S. F. (2002). Effects of prior stress on LPS-induced cytokine
142. and sickness responses. American Journal of Physiology, 24, 24.
Fowell, D., Mcknight, A. J., Powrie, F., Dyke, R., & Mason, D. (1991). Keller, S. E., Schleifer, S. J., & Demetrikopoulos, M. K. (1991). Stress-
Subsets of CD4+ T-cells and their roles in the induction and pre- induced changes in immune function in animals: Hypothalamic-
vention of autoimmunity. Immunology Reviews, 123, 37-64. pituitary-adrenal influences. In R. Ader, D. L. Felten, & N. Cohen
Gao, B., & Tsan, M. F. (2003a). Endotoxin contamination in recombi- (Eds.), Psychoneuroimmunology (2nd ed., pp. 771-788). New York:
nant human heat shock protein 70 (Hsp70) preparation is Academic Press.
responsible for the induction of tumor necrosis factor alpha Keller, S. E., Weiss, J. M., Schleifer, S. J., Miller, N. E., & Stein, M.
release by murine macrophages. Journal of Biological Chemistry, (1981). Suppression of immunity by stress: Effect of a graded
278, 174-179. series of stressors on lymphocyte stimulation in the rat. Science,
Gao, B., & Tsan, M. F. (2003b). Recombinant human heat shock pro- 213, 1397-1400.
tein 60 does not induce the release of tumor necrosis factor alpha Keller, S. E., Weiss, J. M., Schleifer, S. J., Miller, N. E., & Stein, M.
from murine macrophages. Journal of Biological Chemistry, 278, (1983). Stress-induced suppression of immunity in adrenalecto-
22523-22529. mized rats. Science, 221, 1301-1304.
Glaser, R., Kennedy, S., Lafuse, W. P., Bonnneau, R. H., Speicher, C., Kemeny, M. E., & Laudenslager, M. L. (1999). Introduction beyond
Hillhouse, J., et al. (1990). Psychological stress-induced modula- stress: The role of individual difference factors in psychoneuro-
tion of interleukin 2 receptor gene expression and interleukin 2 immunology. Brain, Behavior, and Immunity, 13, 73-75.
production in peripheral blood leukocytes. Archives of General Psy- Kiecolt-Glaser, J. K., Dura, J. R., Speicher, C. E., Trask, O. J., & Glaser,
chiatry, 47, 707-712. R. (1991). Spousal caregivers of dementia victims: Longitudinal
Goehler, L. E., Gaykema, R. P., Hansen, M. K., Anderson, K., Maier, S. changes in immunity and health. Psychosomatic Medicine, 53, 345-
F., & Watkins, L. R. (2000). Vagal immune-to-brain communica- 362.
Kiecolt-Glaser, J. K., Fisher, L. D., Ogrocki, P., Stout, J. C., Speicher,
tion: A visceral chemosensory pathway. Autonomic Neuroscience:
C. E., & Glaser, R. (1987). Marital quality, marital disruption, and
Basic & Clinical, 85, 49-59.
immune function. Psychosomatic Medicine, 49, 13-34.
Goehler, L. E., Relton, J. K., Dripps, D., Kiechle, R., Tartaglia, N.,
King, Y. T., Lin, C. S., Lin, J. H., & Lee, W. C. (2002). Whole-body
Maier, S. F., et al. (1997). Vagal paraganglia bind biotinylated
hyperthermia-induced thermotolerance is associated with the
interleukin-1 receptor antagonist: A possible mechanism for
induction of heat shock protein 70 in mice. Journal of Experimental
immune-to-brain communication. Brain Research Bulletin, 43, 357-
Biology, 205, 273-278.
364.
Kluger, M. J. (1979). Phylogeny of fever. Federation Proceedings, 38, 30-
Green-Johnson, J. M., Zalcman, S., Vriend, C. Y., Dolina, S., Nance,
34.
D. M., & Greenberg, A. H. (1996). Role of norepinephrine in sup- Kol, A., Lichtman, A. H., Finberg, R. W., Libby, P., & Kurt-Jones, E. A.
pressed IgG production in epilepsy-prone mice. Life Science, 59, (2000). Cutting edge: Heat shock protein (HSP) 60 activates the
1121-1132. innate immune response—CD14 is an essential receptor for
Gross, C., Hansch, D., Gastpar, R., & Multhoff, G. (2003). Interaction HSP60 activation of mononuclear cells. Journal of Immunology, 164,
of heat shock protein 70 peptide with NK cells involves the NK 13-17.
receptor CD94. Biological Chemistry, 384, 267-279. Kregel, K. C., & Moseley, P. L. (1996). Differential effects of exercise
Habich, C., Baumgart, K., Kolb, H., & Burkart, V. (2002). The recep- and heat stress on liver HSP70 accumulation with aging. Journal of
tor for heat shock protein 60 on macrophages is saturable, spe- Applied Physiology, 80, 547-551.
cific, and distinct from receptors for other heat shock proteins. Kusnecov, A. V., Grota, L. J., Schmidt, S. G., Bonneau, R. H., Sheridan,
Journal of Immunology, 168, 569-576. J. F., Glaser, R., et al. (1992). Decreased herpes simplex viral
Harmsen, A. G., & Turney, T. H. (1985). Inhibition of in vivo neutro- immunity and enhanced pathogenesis following stressor adminis-
phil accumulation by stress: Possible role of neutrophil adher- tration in mice. Journal of Neuroimmunology, 38, 129-138.
ence. Inflammation, 9, 9-20. Laudenslager, M. L., & Fleshner, M. (1994). Stress and immunity: Of
Hart, B. L. (1988). The biological basis of the behavior of sick ani- mice, monkeys, models, and mechanisms. In R. Glaser & J. K.
mals. Neuroscience and Biobehavioral Reviews, 12, 123-137. Kielcolt-Glaser (Eds.), The handbook of human stress and immunity
Hartl, F. U. (1996). Molecular chaperones in cellular protein folding. (pp. 161-181). San Diego, CA: Academic Press.
Nature, 381, 571-579. Laudenslager, M. L., Fleshner, M., Hofstadter, P., Held, P. E., Simons,
Heneka, M. T., Gavrilyuk, V., Landreth, G. E., O’Banion, M. K., Wein- L., & Maier, S. F. (1988). Suppression of specific antibody produc-
berg, G., & Feinstein, D. L. (2003). Noradrenergic depletion tion by inescapable shock: Stability under varying conditions.
increases inflammatory responses in brain: Effects on IkappaB Brain, Behavior, and Immunity, 2, 92-101.
and HSP70 expression. Journal of Neurochemistry, 85, 387-398. Laudenslager, M. L., Rasmussen, K. L., Berman, C. M., deBlois, S. T.,
Ianaro, A., O’Donnell, C. A., Di Rosa, M., & Liew, F. Y. (1994). A nitric & Suomi, S. J. (2000). Immune changes in adolescent free-
oxide synthase inhibitor reduces inflammation, down-regulates ranging macaques are influenced by maternal rank. Brain, Behav-
inflammatory cytokines and enhances interleukin-10 production ior, and Immunity, 14, 110.
in carrageenin-induced oedema in mice. Immunology, 82, 370-375. Laudenslager, M. L., Ryan, S. M., Drugan, R. C., Hyson, R. L., & Maier,
Irwin, M., Daniels, M., Bloom, E. T., Smith, T. L., & Weiner, H. (1987). S. F. (1983). Coping and immunosuppression: Inescapable but
Life events, depressive symptoms, and immune function. American not escapable shock suppresses lymphocyte proliferation. Science,
Journal of Psychiatry, 144, 437-441. 221, 568-570.
Irwin, M., Lacher, U., & Caldwell, C. (1992). Depression and reduced Leite de Moraes, M. C., & Dy, M. (1997). Natural killer T cells: A
natural killer cytotoxicity: A longitudinal study of depressed potent cytokine-producing cell population. European Cytokine Net-
patients and control subjects. Psychological Medicine, 22, 1045- work, 8, 229-237.
1050. Lewthwaite, J., Owen, N., Coates, A., Henderson, B., & Steptoe, A.
Johnson, G. B., Brunn, G. J., Tang, A. H., & Platt, J. L. (2003). Evolu- (2002). Circulating human heat shock protein 60 in the plasma of
tionary clues to the functions of the toll-like family as surveillance British civil servants: Relationship to physiological and psycho-
receptors. Trends in Immunology, 24, 19-24. social stress. Circulation, 106, 196-201.
Lysle, D. T., Fecho, K., Maslonek, K. A., & Dykstra, L. A. (1995). Evi- Mercado, A. M., Quan, N., Padgett, D. A., Sheridan, J. F., & Marucha,
dence for the involvement of macrophage-derived nitric oxide in P. T. (2002). Restraint stress alters the expression of interleukin-1
the immunomodulatory effect of morphine and aversive Pavlov- and keratinocyte growth factor at the wound site: An in situ
ian conditioning. Advances in Experimental Medicine and Biology, hybridization study. Journal of Neuroimmunology, 129, 74-83.
373, 141-147. Mesches, M. H., Fleshner, M., Heman, K. L., Rose, G. M., & Diamond,
Lyte, M., Nelson, S. G., & Thompson, M. L. (1990). Innate and adap- D. M. (1999). Exposing rats to a predator blocks primed burst
tive immune responses in a social conflict paradigm. Clinical potentiation in the hippocampus in vitro. Journal of Neuroscience,
Immunology Immunopathology, 57, 137-147. 19, RC18.
MacAry, P. A., Javid, B., Floto, R. A., Smith, K. G., Oehlmann, W., Milligan, E. D., McGorry, M. M., Fleshner, M., Gaykema, R. P. A.,
Singh, M., et al. (2004). HSP70 peptide binding mutants separate Goehler, L. E., Watkins, L. R., et al. (1997). Subdiaphragmatic
antigen delivery from dendritic cell stimulation. Immunity, 20, 95- vagotomy does not prevent fever following intracerebroventric-
106. ular prostaglandin E-2: Further evidence for the importance of
MacKenzie, J. (1896). The production of the so-called “rose cold” by vagal afferents in immune-to-brain communication. Brain
artificial means. American Journal of Medical Science, 91, 45-57.
Research, 766, 240-243.
Mac Micking, J., Xie, Q. W., & Nathan, C. (1997). Nitric oxide and
Moraska, A., Campisi, J., Nguyen, K. T., Maier, S. F., Watkins, L. R., &
macrophage function. Annual Review of Immunology, 15, 323-350.
Fleshner, M. (2002). Elevated IL-1beta contributes to antibody
Maes, M. (1997). Cytokines in obsessive-compulsive disorder. Biologi-
suppression produced by stress. Journal of Applied Physiology, 93,
cal Psychiatry, 42, 1187-1188.
Maes, M. (1999). The inflammatory response system activation 207-215.
model of major depression. In N. Muller (Ed.), Psychiatry, psycho- Morimoto, R. I. (1994). The biology of heat shock proteins and molecular
immunology, and viruses (pp. 55-62). Vienna: Springer-Verlag chaperones. Cold Spring Harbor, NY: Cold Spring Harbor
Wien. Laboratory.
Maes, M., Lin, A. H., Delmeire, L., Van Gastel, A., Kenis, G., De Jongh, Moseley, P. L. (1998). Heat shock proteins and the inflammatory
R., et al. (1999). Elevated serum interleukin-6 (IL-6) and IL-6 response. Annals of the New York Academy of Science, 856, 206-213.
receptor concentrations in posttraumatic stress disorder follow- Mosmann, T. R. (1991). Regulation of immune responses by T-cells
ing accidental man-made traumatic events. Biological Psychiatry, with different cytokine secretion phenotypes: Role of a new cyto-
45, 833-839. kine, cytokine synthesis inhibitory factor (IL10). International
M a g g i , E . ( 1 9 9 8 ) . T h e T H 1 / T H 2 p a r a d i g m i n a l l e r g y. Archives of Allergy and Applied Immunology, 94, 110-115.
Immunotechnology, 3, 233-244. Moynihan, J. A., Ader, R., Grota, L. J., Schachtman, T. R., & Cohen, N.
Maier, S. F. (2003). Bi-directional immune-brain communication: (1990). The effects of stress on the development of immunologi-
Implications for understanding stress, pain, and cognition. Brain, cal memory following low-dose antigen priming in mice. Brain,
Behavior, and Immunity, 17, 69-85. Behavior, and Immunity, 4, 1-12.
Maier, S. F., Fleshner, M., & Watkins, L. R. (1998). Neural, endocrine, Multhoff, G., Mizzen, L., Winchester, C. C., Milner, C. M., Wenk, S.,
and immune mechanisms of stress-induced immunomodulation. Eissner, G., et al. (1999). Heat shock protein 70 (Hsp70) stimu-
In A. Levy (Ed.), New frontiers in stress research: Modulation of brain lates proliferation and cytolytic activity of natural killer cells.
function (pp. 175-185): Amsterdam: Harwood Academic. Experimental Hematology, 27, 1627-1636.
Maier, S. F., Goehler, L. E., Fleshner, M., & Watkins, L. R. (1998). The Multhoff, G., Pfister, K., Gehrmann, M., Hantschel, M., Gross, C.,
role of the vagus nerve in cytokine-to-brain communication. Hafner, M., et al. (2001). A 14-mer Hsp70 peptide stimulates natu-
Annals of the New York Academy of Sciences, 840, 289-300. ral killer (NK) cell activity. Cell Stress Chaperones, 6, 337-344.
Maier, S. F., & Laudenslager, M. L. (1988). Inescapable shock, shock Noursadeghi, M., Bickerstaff, M. C., Herbert, J., Moyes, D., Cohen, J.,
controllability, and mitogen stimulated lymphocyte proliferation. & Pepys, M. B. (2002). Production of granulocyte colony-stimulat-
Brain, Behavior, and Immunity, 2, 87-91. ing factor in the nonspecific acute phase response enhances host
Maier, S. F., Nguyen, K. T., Deak, T., Milligan, E. D., & Watkins, L. R. resistance to bacterial infection. Journal of Immunology, 169, 913-
(1999). Stress, learned helplessness, and brain interleukin-1 beta. 919.
Advances in Experimental Medicine & Biology, 461, 235-249. Ohashi, K., Burkart, V., Flohe, S., & Kolb, H. (2000). Cutting edge:
Maier, S. F., & Watkins, L. R. (1998). Cytokines for psychologists: Heat shock protein 60 is a putative endogenous ligand of the toll-
Implications of bidirectional immune-to-brain communication like receptor-4 complex. Journal of Immunology, 164, 558-561.
for understanding behavior, mood, and cognition. Psychological Oka, T., Oka, K., & Hori, T. (2001). Mechanisms and mediators of psy-
Review, 105, 83-107. chological stress-induced rise in core temperature. Psychosomatic
Maier, S. F., Watkins, L. R., & Fleshner, M. (1994). Psychoneuro-
Medicine, 63, 476-486.
immunology: The interface between behavior, brain, and immu- Padgett, D. A., & Glaser, R. (2003). How stress influences the immune
nity. American Psychologist, 49, 1004-1017.
response. Trends in Immunology, 24, 444-448.
Maloyan, A., & Horowitz, M. (2002). Beta-adrenergic signaling and
Padgett, D. A., Marucha, P. T., & Sheridan, J. F. (1998). Restraint stress
thyroid hormones affect HSP72 expression during heat acclima-
slows cutaneous wound healing in mice. Brain, Behavior, and Immu-
tion. Journal of Applied Physiology, 93, 107-115.
nity, 12, 64-73.
Matz, J. M., LaVoi, K. P., & Blake, M. J. (1996). Adrenergic regulation
Panjwani, N. N., Popova, L., & Srivastava, P. K. (2002). Heat shock
of the heat shock response in brown adipose tissue. Journal of Phar-
macology and Experimental Therapeutics, 277, 1751-1758. proteins gp96 and hsp70 activate the release of nitric oxide by
Matz, J. M., LaVoi, K. P., Moen, R. J., & Blake, M. J. (1996). Cold- APCs. Journal of Immunology, 168, 2997-3003.
induced heat shock protein expression in rat aorta and brown adi- Park, C. R., Campbell, A. M., & Diamond, D. M. (2001). Chronic
pose tissue. Physiology & Behavior, 60, 1369-1374. psychosocial stress impairs learning and memory and increases
Matzinger, P. (1994). Tolerance, danger, and the extended family. sensitivity to yohimbine in adult rats. Biological Psychiatry, 50, 994-
Annual Review of Immunology, 12, 991-1045. 1004.
Matzinger, P. (1998). An innate sense of danger. Seminars in Immunol- Paroo, Z., & Noble, E. G. (1999). Isoproterenol potentiates exercise-
ogy, 10, 399-415. induction of Hsp70 in cardiac and skeletal muscle. Cell Stress
McEwen, B. S. (1998). Stress, adaptation, and disease: Allostasis and Chaperonesd, 4, 199-204.
allostatic load. Annals of the New York Academy of Sciences, 840, 33-44. Paterson, H. M., Murphy, T. J., Purcell, E. J., Shelley, O., Kriynovich,
McEwen, B. S. (2000). The neurobiology of stress: From serendipity S. J., Lien, E., et al. (2003). Injury primes the innate immune sys-
to clinical relevance. Brain Research, 886, 172-189. tem for enhanced toll-like receptor reactivity. Journal of Immunol-
McEwen, B. S., & Stellar, E. (1993). Stress and the individual: Mecha- ogy, 171, 1473-1483.
nisms leading to disease. Archives of Internal Medicine, 153, 2093- Peterson, P. K., Molitor, T. W., & Chao, C. C. (1998). The opioid-
2101. cytokine connection. Journal of Neuroimmunology, 83, 63-69.
Pittet, J. F., Lee, H., Morabito, D., Howard, M. B., Welch, W. J., & Shavit, Y., Lewis, J. W., Terman, G. W., Gale, R. P., & Liebeskind, J. C.
Mackersie, R. C. (2002). Serum levels of Hsp 72 measured early (1984). Opioid peptides mediate the suppressive effect of stress
after trauma correlate with survival. Journal of Trauma, 52, 611-617. on natural killer cell cytotoxicity. Science, 223, 188-190.
Plotnikoff, N., Murgo, A., Faith, R., & Wybran, J. (Ed.). (1991). Stress Shavit, Y., Ryan, S. M., Lewis, J. W., Laudenslager, M. L., Terman,
and immunity. Boca Raton, FL: CRC Press. G. W., Maier, S. F., et al. (1983). Inescapable but not escapable
Pockley, A. G., De Faire, U., Kiessling, R., Lemne, C., Thulin, T., & stress alters immune function. The Physiologist, 26, 64.
Frostegard, J. (2002). Circulating heat shock protein and heat Sher, A., Gazzinelli, R. T., Jankovic, D., Scharton-Kersten, T., Yap, G.,
shock protein antibody levels in established hypertension. Journal & Doherty, T. M. (1998). Cytokines as determinants of disease and
of Hypertension, 20, 1815-1820. disease interactions. Brazilian Journal of Medical & Biological
Pockley, A. G., Georgiades, A., Thulin, T., de Faire, U., & Frostegard, Research, 31, 85-87.
J. (2003). Serum heat shock protein 70 levels predict the develop- Sheridan, J. F. (1998). Norman Cousins Memorial Lecture 1997.
ment of atherosclerosis in subjects with established hypertension. Stress-induced modulation of anti-viral immunity. Brain, Behavior,
Hypertension, 42, 235-238. and Immunity, 12, 1-6.
Powrie, F., & Coffman, R. L. (1993). Cytokine regulation of T-cell Sheridan, J. F., Dobbs, C., Jung, J., Chu, X., Konstantinos, A., Padgett,
function: Potential for therapeutic intervention. Immunology D., et al. (1998). Stress-induced neuroendocrine modulation of
Today, 14, 270-274. viral pathogenesis and immunity. Annals of the New York Academy of
Powrie, F., & Mason, D. (1988). Phenotypic and functional heteroge- Sciences, 840, 803-808.
neity of CD4+ T cells. Immunology Today, 9, 274-277. Sheridan, J. F., Stark, J. L., Avitsur, R., & Padgett, D. A. (2000). Social
Prohaszka, Z., Singh, M., Nagy, K., Kiss, E., Lakos, G., Duba, J., et al. disruption, immunity, and susceptibility to viral infection: Role of
(2002). Heat shock protein 70 is a potent activator of the human glucocorticoid insensitivity and NGF. Annals of the New York Acad-
complement system. Cell Stress and Chaperones, 7, 17-22. emy of Sciences, 917, 894-905.
Pugh, C. R., Fleshner, M., Tremblay, D., & Rudy, J. W. (1997). A selec- Smith, A., Vollmer-Conna, U., Bennett, B., Wakefield, D., Hickie, I., &
tive role for corticosterone in contextual fear conditioning. Behav- Lloyd, A. (2004). The relationship between distress and the devel-
ioral Neuroscience, 111, 503-511. opment of a primary immune response to a novel antigen. Brain,
Raber, J., Sorg, O., Horn, T. F., Yu, N., Koob, G. F., Campbell, I. L., Behavior, and Immunity, 18, 65-75.
et al. (1998). Inflammatory cytokines: Putative regulators of Smith, J. A., & Pyne, D. B. (1997). Exercise, training, and neutrophil
neuronal and neuro-endocrine function. Brain Research Reviews, function. Exercise Immunology Reviews, 3, 96-116.
26, 320-326. Smith, T. P., Kennedy, S. L., & Fleshner, M. (in press). Influence of age
Redaelli, C. A., Wagner, M., Kulli, C., Tian, Y. H., Kubulus, D., and physical activity on the primary in vivo antibody and T-cell
Mazzucchelli, L., et al. (2001). Hyperthermia-induced HSP mediated responses in men. Journal of Applied Physiology.
expression correlates with improved rat renal isograft viability and Solomon, G. F. (1993). Whither psychoneuroimmunology: A new era
survival in kidneys harvested from non-heart-beating donors. of immunology, of psychosomatic medicine, and of neuroscience.
Transplant International, 14, 351-360. Brain, Behavior, and Immunity, 7, 352-366.
Reed, R. C., & Nicchitta, C. V. (2000). Chaperone-mediated cross- Solomon, G. F., & Moos, R. H. (1964). Emotions, immunity, and dis-
priming: A hitchhiker’s guide to vesicle transport. International ease. Archives of General Psychiatry, 11, 657-671.
Journal of Molecular Medicine, 6, 259-264. Solomon, G. F., Segerstrom, S. C., Grohr, P., Kemeny, M., & Fahey, J.
Ritossa, F. (1962). A new puffing pattern induced by temperature (1997). Shaking up immunity: Psychological and immunologic
shock and DNP in Drosophila. Experientia, 15, 571-573. changes after a natural disaster. Psychosomatic Medicine, 59, 114-
Rojas, I. G., Padgett, D. A., Sheridan, J. F., & Marucha, P. T. (2002). 127.
Stress-induced susceptibility to bacterial infection during cutane- Sondermann, H., Becker, T., Mayhew, M., Wieland, F., & Hartl, F. U.
ous wound healing. Brain, Behavior, and Immunity, 16, 74-84. (2000). Characterization of a receptor for heat shock protein 70
Rudy, J. W. (1993). Contextual conditioning and auditory cue condi- on macrophages and monocytes. Biological Chemistry, 381, 1165-
tioning dissociate during development. Behavioral Neuroscience, 1174.
107, 887-891. Srivastava, P. (2002). Interaction of heat shock proteins with peptides
Rudy, J. W. (1994). Ontogeny of context-specific latent inhibition and antigen presenting cells: Chaperoning of the innate and
of conditioned fear: Implications for configural associations the- adaptive immune responses. Annual Reviews of Immunology, 20,
ory and hippocampal formation development. Developmental 395-425.
Psychobiology, 27, 367-379. Stefanski, V., Solomon, G. F., Kling, A. S., Thomas, J., & Plaeger, S.
Rudy, J. W., & Morledge, P. (1994). Ontogeny of contextual fear con- (1996). Impact of social confrontation on rat CD4 T cells bearing
ditioning in rats: Implications for consolidation, infantile amne- different CD45R isoforms. Brain, Behavior, and Immunity, 10, 364-
sia, and hippocampal system function. Behavioral Neuroscience, 379.
108, 227-234. Sun, L., Chang, J., Kirchhoff, S. R., & Knowlton, A. A. (2000). Activa-
Rudy, J. W., & O’Reilly, R. C. (1999). Contextual fear conditioning, tion of HSF and selective increase in heat-shock proteins by acute
conjunctive representations, pattern completion, and the hippo- dexamethasone treatment. American Journal of Physiology, 278,
campus. Behavioral Neuroscience, 113, 867-880. H1091-1097.
Santoro, M. G. (2000). Heat shock factors and the control of the stress Takaki, A., Huang, Q. H., Somogyvari-Vigh, A., & Arimura, A. (1994).
response. Biochemistry and Pharmacology, 59, 55-63. Immobilization stress may increase plasma interleukin-6 via cen-
Schleifer, S., Keller, S. E., Camerino, M., Thornton, J. C., & Stein, M. tral and peripheral catecholamines. Neuroimmunomodulation, 1,
(1983). Suppression of lymphocyte stimulation following bereave- 335-342.
ment. Journal of the American Medical Association, 250, 374-377. Thomas, G., Souil, E., Richard, M. J., Saunier, B., Polla, B. S., &
Segerstrom, S. C., Kemeny, M. E., & Laudenslager, M. L. (2001). Indi- Bachelet, M. (2002). Hyperthermia assists survival of astrocytes
vidual difference factors in psychoneuroimmunology. In R. Ader, from oxidative-mediated necrotic cell death. Cellular and Molecu-
D. L. Felten, & N. Cohen (Eds.), Psychoneuroimmunology (3rd ed., lar Biology, 48, 191-198.
pp. 87-110). New York: Academic Press. Tissieres, A., Mitchell, H. K., & Tracy, U. (1974). Protein synthesis in
Segerstrom, S. C., Solomon, G. F., Kemeny, M. E., & Fahey, J. L. salivary glands of Drosophila melanogaster: Relation to chromosome
(1998). Relationship of worry to immune sequelae of the puffs. Journal of Molecular Biology, 84, 389-398.
Northridge earthquake. Journal of Behavioral Medicine, 21, 433-450. Todryk, S. M., Melcher, A. A., Dalgleish, A. G., & Vile, R. G. (2000).
Selye, H. (1946). The general adaptation syndrome and diseases of Heat shock proteins refine the danger theory. Immunology, 99, 334-
adaptation. Journal of Clinical Endocrinology, 6, 117-230. 337.
Seong, S.-Y., & Matzinger, P. (2004). Hydrophobicity: An ancient dam- Tomioka, H., & Saito, H. (1992). Characterization of immunosup-
age associated molecular pattern that initiates innate immune pressive functions of murine peritoneal macrophages induced
responses. Nature Reviews, 4, 469-478. with various agents. Journal of Leukocyte Biology, 51, 24-31.
Udelsman, R., Blake, M. J., Stagg, C. A., & Holbrook, N. J. (1994). Watkins, L. R., Maier, S. F., & Goehler, L. E. (1995a). Cytokine-to-
Endocrine control of stress-induced heat shock protein 70 expres- brain communication: A review and analysis of alternative mecha-
sion in vivo. Surgery, 115, 611-616. nisms. Life Sciences, 57, 1011-1026.
Udelsman, R., Blake, M. J., Stagg, C. A., Li, D. G., Putney, D. J., & Watkins, L. R., Maier, S. F., & Goehler, L. E. (1995b). Immune activa-
Holbrook, N. J. (1993). Vascular heat shock protein expression in tion: The role of pro-inflammatory cytokines in inflammation, ill-
response to stress: Endocrine and autonomic regulation of this ness responses and pathological pain states. Pain, 63, 289-302.
age-dependent response. Journal of Clinical Investigation, 91, 465- Watkins, L. R., Milligan, E. D., & Maier, S. F. (2001). Glial activation: A
473. driving force for pathological pain. Trends in Neuroscience, 24, 450-
Udelsman, R., Li, D. G., Stagg, C. A., Gordon, C. B., & Kvetnansky, R. 455.
(1994). Adrenergic regulation of adrenal and aortic heat shock Watkins, L. R., Nguyen, K. T., Lee, J. E., & Maier, S. F. (1999). Dynamic
protein. Surgery, 116, 177-182. regulation of proinflammatory cytokines. Advances in Experimental
Vabulas, R. M., Ahmad-Nejad, P., Ghose, S., Kirschning, C. J., Issels, Medicine and Biology, 461, 153-178.
R. D., & Wagner, H. (2002). HSP70 as endogenous stimulus of the Weiss, B., Laties, V. G., & Weiss, A. B. (1967). Behavioral thermoregu-
toll/interleukin-1 receptor signal pathway. Journal of Biological lation by cats with pyrogen-induced fever. Archives Internationales
Chemistry, 277, 15107-15112. de Pharmacodynamie et de Therapie, 165, 467-475.
Valen, G., Kawakami, T., Tahepold, P., Dumitrescu, A., Lowbeer, C., & Whiteside, T. L., & Herberman, R. B. (1989). The role of natural
Vaage, J. (2000). Glucocorticoid pretreatment protects cardiac killer cells in human disease. Clinical Immunology Immunopathology,
function and induces cardiac heat shock protein 72. American Jour- 53, 1-23.
nal of Physiology, 279, H836-843. Whiteside, T. L., & Herberman, R. B. (1995). The role of natural killer
Visintin, A., Mazzoni, A., Spitzer, J. H., Wyllie, D. H., Dower, S. K., & cells in immune surveillance of cancer. Current Opinions in Immu-
Segal, D. M. (2001). Regulation of toll-like receptors in human nology, 7, 704-710.
monocytes and dendritic cells. Journal of Immunology, 166, 249-255. Wilson, C. J., Finch, C. E., & Cohen, H. J. (2002). Cytokines and cogni-
Walsh, R. C., Koukoulas, I., Garnham, A., Moseley, P. L., Hargreaves, tion: The case for a head-to-toe inflammatory paradigm. Journal of
M., & Febbraio, M. A. (2001). Exercise increases serum Hsp72 in the American Geriatrics Society, 50, 2041-2056.
humans. Cell Stress and Chaperones, 6, 386-393. Wright, B. H., Corton, J. M., El-Nahas, A. M., Wood, R. F., & Pockley,
Watkins, L. R., Goehler, L. E., Relton, J. K., Tartaglia, N., Silbert, L., A. G. (2000). Elevated levels of circulating heat shock protein 70
Martin, D., et al. (1995). Blockade of interleukin-1 induced hyper- (Hsp70) in peripheral and renal vascular disease. Heart Vessels, 15,
thermia by subdiaphragmatic vagotomy: Evidence for vagal medi- 18-22.
ation of immune brain communication. Neuroscience Letters, 183, Zalcman, S., & Anisman, H. (1993). Acute and chronic stressor effects
27-31. on the antibody response to sheep red blood cells. Pharmacology
Watkins, L. R., & Maier, S. F. (1999). Implications of immune-to-brain Biochemistry and Behavior, 46, 445-452.
communication for sickness and pain. Proceedings of the National Zidel, Z., & Masek, K. (1998). Erratic behavior of nitric oxide within
Academy of Sciences of the United States of America, 96, 7710-7713. the immune system: Illustrative review of conflicting data and
their immunopharmacological aspects. International Journal of
Immunopharmacology, 20, 3.
View publication stats

Psychoneuroimmunology Then and Now

Uploaded by

Copyright:

Available Formats

Psychoneuroimmunology Then and Now

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Psychoneuroimmunology Then and Now

Uploaded by

Copyright:

Available Formats

See discussions, stats, and author profiles for this publication at: https://www.researchgate.

Psychoneuroimmunology: Then and Now

Article in Behavioral and Cognitive Neuroscience Reviews · June 2004

Monika Fleshner Mark L Laudenslager

SEE PROFILE SEE PROFILE

Exercise, stress resistance and central serotonergic systems View project

The user has requested enhancement of the downloaded file.

longed, appeared detrimental to the health of the organ-

View publication stats

You might also like