Theoharis C.

Theoharides Differential release of mast cell

Duraisamy Kempuraj
Michael Tagen
mediators and the pathogenesis of
Pio Conti inflammation
Dimitris Kalogeromitros

Authors’ addresses Summary: Mast cells are well known for their involvement in allergic and
Theoharis C. Theoharides1,2,3,4, Duraisamy Kempuraj1, Michael Tagen1, anaphylactic reactions, during which immunoglobulin E (IgE) receptor
Pio Conti5, Dimitris Kalogeromitros4 (FceRI) aggregation leads to exocytosis of the content of secretory granules
1
Laboratory of Molecular Immunopharmacology and Drug (1000 nm), commonly known as degranulation, and secretion of multiple
Discovery, Department of Pharmacology and Experimental mediators. Recent findings implicate mast cells also in inflammatory
Therapeutics, Tufts University School of Medicine diseases, such as multiple sclerosis, where mast cells appear to be intact by
and Tufts – New England Medical Center, Boston, MA, USA. light microscopy. Mast cells can be activated by bacterial or viral antigens,
2
Department of Biochemistry, Tufts University School of cytokines, growth factors, and hormones, leading to differential release of
Medicine and Tufts – New England Medical Center, Boston, distinct mediators without degranulation. This process appears to involve
MA, USA. de novo synthesis of mediators, such as interleukin-6 and vascular endothelial
3
Department of Internal Medicine, Tufts University School growth factor, with release through secretory vesicles (50 nm), similar to
of Medicine and Tufts – New England Medical Center, those in synaptic transmission. Moreover, the signal transduction steps
Boston, MA, USA. necessary for this process appear to be largely distinct from those known in
4
Allergy Section, Attikon Hospital, Athens, Medical School, FceRI-dependent degranulation. How these differential mast cell responses
Athens, Greece. are controlled is still unresolved. No clinically available pharmacological
5
Immunology Division, Department of Cancer and Neuro- agents can inhibit either degranulation or mast cell mediator release.
science, Chieti University Medical School, Chieti, Italy. Understanding this process could help develop mast cell inhibitors of
selective mediator release with novel therapeutic applications.
Correspondence to:
Theoharis C. Theoharides, PhD, MD
Keywords: brain, inflammation, mast cells, multiple sclerosis, stress, vascular permeability
Department of Pharmacology and Experimental
Therapeutics Tufts University School of Medicine
136 Harrison Avenue
Boston, MA 02111, USA
Tel.: (617) 636 6866 Introduction
Fax: (617) 636 2456
E-mail: [email protected] Mast cells derive from a distinct precursor in the bone marrow
Acknowledgements
(1, 2) and mature under the influence of stem cell factor (SCF)
Aspects of the work discussed were supported in part by and various cytokines (3). Depending on their location or stage
grants awarded to T. C. T. from the Multiple Sclerosis of maturation, mast cells express different amounts of surface
Society (RG-1961-A-1), NIH (NS38326, AR47652,
DK62861, DK42409, DK 44816, DK and NS55681), DOD
antigens, some of which are involved in activation and others in
(BC024430), and Theta Biomedical Consulting and cell recognition (4). Mast cells also express numerous chemo-
Development Co., Inc. (Brookline, MA, USA). We thank kine receptors that do not induce degranulation but could
Ms Jessica Christian for her patience and word processing
skills. T. C. T. discloses that he has been awarded US patent
render them susceptible to human immunodeficiency virus
No. 5,250,529; No. 6,020,305; No. 5,648,350; No. infection (5). SCF or c-kit ligand also acts as a mast cell
5,855,884; No. 5,821,259; No. 5,994,357; No. chemoattractant, in addition to nerve growth factor (NGF) (6),
6,624,148; No. 6,689,748; No. 6,984,667; No.
7,115,278 and pending US patent application No. 10/
monocyte chemoattractant protein-1 (MCP-1), and a molecule
811,826, as well as EPO patent No. 1365777, covering the called ‘regulated upon activation, normal T-cell expressed and
role of mast cells in the diseases discussed herein. secreted’ (RANTES) (7). Mast cells are necessary for the
development of allergic reactions, through cross-linking of
Immunological Reviews 2007
Vol. 217: 65–78
their high-affinity surface receptors for immunoglobulin (Ig) E
Printed in Singapore. All rights reserved (FceRI) (8), leading to degranulation and the release of vaso-
ª 2007 The Authors active, proinflammatory, and nociceptive mediators; these in-
Journal compilation ª 2007 Blackwell Munksgaard
Immunological Reviews clude histamine, interleukin (IL)-6, IL-8, IL-13, prostaglandin
0105-2896 D2, leukotriene C4 (LTC4), tumor necrosis factor-a (TNF-a),

65
Theoharides et al
Mast cell mediator release in inflammation

tryptase, and vascular endothelial growth factor (VEGF) (3, 9, (12). IL-4 enhances SCF-dependent mast cell proliferation and
10) (Table 1). SCF enhances FceRI-induced degranulation and shifts IgE-dependent cytokine production in mature human
cytokine production, although it does not induce degranulation mast cells to increased release of T-helper 2 cell (Th2) cyto-
on its own (11). kines such as IL-3, IL-5, and IL-13 but not IL-6 expression (13).
The types of cytokines produced are not fixed. For instance, Mast cells in the presence of SCF produce predominantly
human umbilical cord-blood-derived mast cells (hCBMCs) proinflammatory cytokines, whereas in the presence of SCF
primed with IL-5 released fivefold higher levels of TNF-a, IL-5, and IL-4, also produce Th2 cytokines (14).
macrophage inflammatory protein-1a (MIP-1a), and granulo- In addition to allergic triggers, mast cells can be activated by
cyte–macrophage colony-stimulating factor (GM-CSF); unlike adenosine, anaphylatoxins, antibody light chains, bacterial and
IL-4, IL-5 did not enhance FceRI-dependent histamine release viral antigens, cytokines, endothelin, and neuropeptides (15).

Table 1. Mast cell mediators

Mediators Major pathophysiologic effects

Prestored
Biogenic amines*
Histamine Vasodilation, angiogenesis, mitogenesis, suppressor T-cell activation
5-Hydroxytryptamine (5-HT, serotonin) Leukocyte regulation, vasoconstriction, pain
Chemokines
IL-8, MCP-1, MCP-3, MCP-4, RANTES Chemoattraction and tissue infiltration of leukocytes
Enzymes
Arylsulfatases Lipid/proteoglycan hydrolysis
Carboxypeptidase A Peptide processing
Pro-caspase 3, 4 Peptide processing
Chymase Tissue damage, pain, angiotensin II synthesis
b-Hexosaminidase Carbohydrate processing
Kinogenases Synthesis of kinins, pain
Metalloproteinases Tissue damage
Nitric oxide synthase NO production
Peroxidases Free oxygen radical production
Phospholipases Arachidonic acid generation, inflammation
Tryptase Activation of PAR, inflammation, pain, tissue damage, degradation of
antigens and peptides
Polypeptides
CRH Inflammation, vasodilation, mast cell VEGF release
Endorphins Analgesia, modulation of leukocyte activity
Endothelin Sepsis
Kinins (bradykinin) Inflammation, pain, vasodilation, mast cell trigger
Somatostatin (SRIF) Anti-inflammatory (?), mast cell trigger
Substance P (SP) Inflammation, pain, mast cell trigger
Urocortin (Ucn) Inflammation, vasodilation, mast cell activation
VEGF Neovascularization, vasodilation
Vasoactive intestinal peptide Vasodilation, mast cell trigger
Proteoglycans
Chondroitin sulfate Connective tissue component, anti-inflammatory, mast cell inhibitor
Heparin Angiogenesis, NGF stabilization, mast cell inhibitor
Hyaluronic acid Connective tissue, component
De novo synthesized
Cytokines
IL-1, -3, -4, -5, -6, -9, -10, -13, -16 Inflammation, leukocyte migration, pain
IFN-g, MIF, TNF-a Inflammation, leukocyte proliferation/activation
Growth Factors
SCF, GM-CSF, GnRH-I b-FGF, NGF, VEGF Growth of a variety of cells, mast cell proliferation
Phospholipid metabolites
LTB4 Leukocyte chemotaxis
LTC4 Vasoconstriction, pain
PAF Platelet activation, vasodilation, inflammation
PGD2 Bronchoconstriction, pain
NO Vasodilation, neuromodulation

b-FGF, fibroblast growth factor; GnRH, gonadotropin-releasing hormone-I; LTB4, leukotriene B4; MIF, macrophage inflammatory factor; NO, nitric oxide;
PAF, platelet-activating factor; PGD2, prostaglandin D2; SRIF, somatomedin release inhibitory factor, somatostatin; TGF-b, transforming growth factor-b.
*Mast cell can take up biogenic amines, store them, and secrete them.

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Simultaneous addition of C3a and IgG led to increased (30), not surprising as the brain is not known to develop
degranulation of human mast cells (16). Monomeric IgE has allergic reactions and as IgE does not cross the blood–brain
been shown to reduce histamine, LTC, and IL-8 and maintain barrier (BBB). Moreover, mast cells are rarely seen to
histamine release from human cultured lung mast cells (17). degranulate during autoimmune (31) or inflammatory pro-
Ig-free light chains can also elicit immediate hypersensitivity- cesses (32). The only way to explain how this versatile cell may
like responses (18, 19) with subsequent T-cell-mediated im- regulate immune responses or how it could be involved in
mune responses (20). The anti-bacterial peptides, human b- inflammatory diseases without causing anaphylactic shock is
defensins, can reunite mast cells and induce degranulation (21). through ‘differential’ or ‘selective’ release of mediators (33)
Consequently, mast cells could play an important role in innate without degranulation (34, 35).
or acquired immunity (3, 22, 23) as well as limit endothelin- Mast cells could release the content of individual granules
related toxicity during bacterial infections (24). Increasing (36) that may contain different mediators at different locations.
evidence also indicates that mast cells are critical for the A number of innate and exogenous molecules can trigger mast
pathogenesis of a number of inflammatory diseases (Table 2), cells to release key mediators differentially or selectively (34,
but this role could only be achieved if mast cells could release 35, 37) (Table 3). This process was originally reported for
selective mediators without degranulation (Fig. 1) that would serotonin, which could be released without histamine (33).
otherwise lead to allergic or anaphylactic reactions (15). Serotonin could also be released without arachidonic acid
Mast cells are also known to infiltrate a number of tumors, metabolites (38–40). Differential release of eicosanoids was
but they appear intact with light microscopy and are considered also reported without histamine (39). Others also showed
to induce angiogenesis and provide an environment conducive differential release of IL-6 in response to bacterial lipopolysac-
to cancer growth (25–28). Angiogenesis in endometrial cancer charide (LPS), in the presence of the phosphatidylinositol
increases with tumor progression, and angiogenic tryptase 3-kinase (PI3K) inhibitor wortmannin, or triggered by SCF
secreted by host mast cells cooperates in this induction (29). (41–44). IL-1 can also stimulate human mast cells to release IL-
6 selectively (45). Recently, corticotropin-releasing hormone
(CRH) was shown to stimulate selective release of VEGF without
Differential release of mast cell mediators
degranulation and histamine or tryptase release from the human
Mast cells are ubiquitous in the body, including the brain where mast cell line (HMC-1) and hCBMCs (46). Prostaglandin E2
they do not express FceRI protein under normal conditions (PGE2) also induced selective VEGF release (47) as well as
release of MCP-1 without degranulation (48). Yet, PGE2
inhibited FceRI-induced histamine release from human lung
Table 2. Inflammatory diseases involving and mast cell activation mast cells (49). Strangely, PGE2 stimulated skin mast cell
Disease Major pathophysiologic role
degranulation in older but not in younger mice (50). Stromal-
cell-derived factor-1a can selectively produce IL-8 from human
Asthma Bronchoconstriction, pulmonary
inflammation mast cells also without degranulation (51). Activation of human
Atopic dermatitis Skin vasodilation, T-cell recruitment, cultured mast cells by CD40 ligand was recently shown to lead
inflammation, itching
Coronary artery disease Coronary inflammation, myocardial
to release of the chemokines IL-8 and MIP-1 without
ischemia degranulation (52). Interestingly, nanoreceptor-type protein
Chronic fatigue syndrome Brain inflammation, exhaustion
kinase-deficient mast cells could not generate IL-6, TNF, or
Chronic prostatitis Prostate inflammation, pain
Fibromyalgia Muscle inflammation, pain MCP-1 during FceRI aggregation, but IL-13 production was
Inflammatory bowel Gastrointestinal inflammation, pain intact, suggesting divergent regulatory pathways (53).
disease
Interstitial cystitis Bladder mucosal damage, inflammation, Toll-like receptors (TLRs) are critical in innate and acquired
pain immunity (54–56). Rodent mast cells express TLR4, which
Migraines Meningeal vasodilation, inflammation,
pain binds LPS and induces the release of TNF-a without
Multiple sclerosis Increased BBB permeability, degranulation, while peptidoglycan induces degranulation
brain inflammation,
demyelination, T-cell activation and histamine release through TLR2 (57, 58). LPS also induced
Neurofibromatosis Skin nerve growth, fibrosis secretion of IL-5, IL-10, and IL-13 but not GM-CSF, IL-1, or
Osteoarthritis Articular erosion, inflammation, pain
Psoriasis Skin inflammation, T-cell recruitment LTC4 (58, 59). Activation of TLRs appears to be even more
Rheumatoid arthritis Joint inflammation, cartilage erosion complicated, as LPS produced TNF-a, IL-1, IL-6, and IL-13 but
Rhinosinusitis Nasal and sinus inflammation
not IL-4 or IL-5, while TLR2 activation produced IL-4, IL-6, and

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Mast cell mediator release in inflammation

Fig. 1. Schematic representation of some of

the triggers permitting differential release
of mast cell mediators and their contribu-
tion to inflammation. M, macrophages; T,
T cells.

IL-13 but not IL-1 (60). Antigen apparently could have Low-intensity stimulation of FceRI with IgE plus anti-IgE or
a synergistic action with TLR2 and TLR4 in enhancing cytokine IgE plus low antigen positively regulates degranulation and
production from rodent mast cells (61). cytokine production, whereas Lyn (an sarcoma inducing gene
Fetal rat-skin-derived mast cells express viral TLR3, TLR7, of rous sarcoma virus (Src) family kinase) works as a negative
and TLR9, and activation by polyoligodeoxynucleotide and regulator of high-intensity stimulation with IgE plus high
CpG induced release of TNF-a, IL-6, RANTES, and MIP, again antigen (66). However, Lyn/ mice had increased FceRI
without degranulation (62). Human mast cells can produce expression, circulating histamine, and eosinophilia (67).
IL-6 through viral TLR9 activation (63), while they produce Suboptimal antigen challenge of human mast cells led to FceRI
interferon (IFN) in response to double-stranded RNA through unresponsiveness that correlated to reduced spleen tyrosine
TLR3 (64). We showed that HMC-1 expresses TLR3, TLR5, kinase (Syk) levels (68). Suboptimal IgE concentrations could
TLR7, and TLR9 and that TLR9 expression was increased in induce actin assembly that blocked degranulation (69).
response to its activation (65). No specific ultrastructural or However, low antigen sill permitted MCP-1 release (70).
biochemical events have so far been defined in TLR-induced Mizolastine, a histamine-1 receptor antagonist, inhibits LTC4
release of cytokines, although they may be able to predispose synthesis in human mast cells and basophils, but it enhances
or enhance allergic responses. These results suggest that histamine and IL-4 release only from anti-IgE-stimulated
bacterial or viral infections could lead to aberrant inflamma- basophils (71). LPS enhances production of IL-9 and IL-13 but
tory responses through mast cell activation without systemic not IL-4 from primary murine bone-marrow-derived mast cells
signs of allergy. activated with ionomycin or IgG–antigen (72). IL-4 enhances

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Table 3. Examples of differential release of mast cell mediators

Mast cell
Stimuli type used Mediators released Mediators not released Physiological importance References

Endogenous
CD4 ligands hCBMC IL-8, MCP-1 Histamine Leukocyte chemotaxis Fischer et al. (52)
CD8 ligands RPMC TNF-a, NO Histamine T-cell interactions Lin et al. (185)
CRHR-1 hCBMC VEGF H, tryptase, IL-8 Inflammation Cao et al. (144)
CRHR-2 hCBMC IL-6 H, tryptase, IL-8, VEGF Inflammation Papadopoulou et al. (186)
Endothelin-1-3 RMMC TNF-a, IL-12[* IL-4, IL-10, IL-13Y* Th1 immunity Coulombe et al. (187)
IL-1 hCBMC IL-6, IL-8, TNF H, tryptase Inflammation Kandere-Grzybowska et al. (45)
IL-1b RPMC NO PAF, H Inflammation Hogaboam et al. (188)
IL-12 RPMC IFN-g Histamine Th1 immunity Gupta et al. (189)
LTC4/LTD4 IL-4-primed TNF-a, MIP-1a, IL-5 H Inflammation Mellor et al. (190)
hCBMC
Monomeric IgE BMMC IL-6 H, LTC4 Mast cell survival Kalesnikoff et al. (191)
PGE2 RPMC IL-6 H, TNF-a Inflammation Leal-Berumen et al. (192)
PGE2 hCBMC MCP-1 No degranulation Angiogenesis Nakayama et al. (48)
SCF BMMC IL-6 H, LTC4, TNF-a Mast cell development Gagari et al. (43)
SDF-a hCBMC IL-8 H, GM-CSF, IFN-g, Endothelial transmigration Lin et al. (51)
IL-1b
Suboptimal FceRI BMMC MCP-1, H low IL-10, H Chemokines >> Gonzalez-Espinosa et al. (70)
stimulation Cytokines /HA
Thrombin BMMC IL-6 5-HT, TNF-a Coronary inflammation Gordon et al. (193)
Exogenous
Amitriptyline RPMC Serotonin Histamine Headaches Theoharides et al. (33)
Cholera toxin RPMC IL-6 TNF-a Inflammation Leal-Berumen et al. (194)
CpG DNA BMMC TNF-a, IL-6 H, IL-4, IL-12, Host response
GM-CSF, IFN-g to bacteria
Helicobacter pylori BMMC IL-6, IL-8, TNF H Gastric injury Supajatura et al. (60)
VacA toxin
LPS RPMC IL-6 H Bacterial infection Leal-Berumen et al. (41)
PMA BMMC VPF/VEGF 5-HT Angiogenesis Boesiger et al. (10)
Peptidoglycan hCBMC GM-CSF, b-hexosaminidase, IL-6 Exacerbation of asthma McCurdy et al. (58)
IL-1b, RANTES,
LTC4

BMMC, bone marrow-derived mast cells (rodent); CRH, corticotropin releasing hormone; GM-CSF, granulocyte-macrophage-colony stimulating factor;
H, histamine; 5-HT; 5-hydroxytryptamine; LPS, lipopolysaccharid; LTD4, leukotriene D4; RPMC, rat peritoneal mast cells; PMA, phorbol myristate acetate;
SCF, stem cell factor; SDF, stromal cell-derived factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; VPF, vascular permeability
factor.

whereas INF-g inhibits the FceRI-mediated production of MIP- dependent exocytosis (75). This process involved SNAP-23
1a, IL-8, and GM-CSF from human mast cells (73). B-cell phosphorylation (76). Mast cells can undergo ultrastructural
lymphoma 10 (Bcl10) and mucosal-associated lymphoid tissue- alterations of their electron-dense granular core indicative of
1 (MALT-1) are identified as a key regulators of mast secretion but without degranulation, a process that has been
cell signaling. Mice deficient for either protein show severely termed ‘activation’ (77–79), ‘intragranular activation’ (80), or
impaired IgE-dependent late-phase anaphylactic reactions. ‘piecemeal’ degranulation (81) (Fig. 2). Piecemeal degranula-
Mast cells from these animals neither activate NF-kB nor produce tion was recently shown to involve vesicular transport of
TNF-a or IL-6 upon FceRI signaling, while degranulation and LT secretory granules contents (82). However, these ultrastruc-
secretion are normal. Thus, Bcl10 and MALT-1 are essential tural observations have not been linked to release of a specific
positive mediators of FceRI-dependent mast cell activation that mediator. We had shown that differential release of serotonin
selectively uncouple NF-kB-induced proinflammatory cytokine involved its being sequestered from secretory granules inside
production from degranulation and LT synthesis (74). vesicles containing high-affinity serotonin-binding proteins
from which it was then released (83). More recently, we
showed that IL-6 release in response to IL-1 involves 40–80 nm
Mechanisms involved
vesicles unrelated to the secretory granules (800–1000 nm),
FceRI-induced mast cell degranulation requires calcium- and IL-4 release from these vesicles did not require extracellular
independent granule translocation to the surface but calcium- calcium ions (45). Selective mediator segregation in and release

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Fig. 2. Mast cells in inflammatory diseases.

(A) Degranulated human LAD2 cell in
response to 0.01 mM MBP. (B) Activated
bladder mast cell from a patient with the
inflammatory disease interstitial cystitis. (C)
An activated brain mast cell from monkey
EAE, with prominent intragranular changes.
(D) Section of one hCBMC after cryoimmu-
noelectron microscopy showing a vesicle
(arrow) releasing a group of gold-labeled
antibody-recognized selectively release IL-6
molecules in response to IL-1 (100 nM).

from specific vesicles could be accomplished through corre- involved only protein kinase A (PKA) and p38 MAPK activation
sponding ‘non-functional’ receptors expressed on such vesicles, (46). Adapter complexes appear to segregate FceRI-dependent
as shown for eosinophils (84). activation of mast cells; for instance, the Bcl10–MALT-1 complex
The downstream pathway steps involved in FceRI-induced or permits IL-6 and TNF-a release without degranulation (90).
peptide-induced degranulation are well known and appear to be Gene array analysis of human mast cells activated by IgE
distinct from those necessary in differential secretion (Table 4). showed overexpression of numerous, mostly inflammation-
For instance, FceRI aggregation requires extracellular calcium related genes (91). In contrast, among the genes that were
ions as well as PI3K, extracellular-signal-regulated kinase, c-Jun upregulated more than 1.5-fold after CRH stimulation (6 h)
N-terminal kinase (JNK), NF-kB, and protein kinase C (PKC) were those related to vesicular trafficking and release (Table 5)
activation, although PKC isozyme-e was recently shown to be (unpublished data).
redundant (85, 86). FceRI aggregation leads to production of
phosphatidyl inositol-3,4,5-triphosphate through the action of
Multiple sclerosis
PI3K, which is inhibited by phosphatase and the molecule called
‘tensin homologue deleted on chromosome ten’ (PTEN); PTEN One disease where mast cells have been implicated without
knockdown induced constitutive cytokine production without degranulation is multiple sclerosis (MS), a demyelinating
degranulation along with phosphorylation of AKT, p38 condition (92, 93) involving brain infiltration by lymphocytes
mitogen-activated protein kinase (MAPK) and JNK (87). (94, 95). The role of CD4þ T cells is well documented in MS,
Secretion in response to NGF appears to be regulated by tyrosine but this CD4þ Th1 model has recently been questioned (96).
kinase (TK), PI3K, and PKC, but not MAPK, while secretion by Increasing evidence implicates Th2 processes typically associ-
compound 48/80 requires PLC, TK, MAPK, and PKC (88). In ated with allergic reactions (97–99). For instance, myelin basic
contrast, IL-1 stimulation of mast cells was extracellular calcium protein (MBP) induced homogeneic mast cell activation and
independent and involved p38 MAPK, NF-kB, and PKCy brain demyelination (100). Virally induced encephalomyelitis
isozyme activation (89). CRH activation of selective mast cell could not develop in W/Wv mast-cell-deficient mice (101,
VEGF release was also extracellular calcium independent but 102), and experimental allergic encephalomyelitis (EAE) was

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Table 4. Signaling steps involved in mast cell degranulation and Table 6. Possible mast cell actions in MS
differential secretion
d
Adhesion molecule induction
Triggers d
BBB disruption
d
Demyelination
Steps involved FceRI NGF 48/80 CRH IL-1 d
Fibrosis and plaque formation
d
Macrophage recruitment
Ca2þ* þ þ    d
PAR-related inflammation
PI3K þ þ  ? ? d
T-cell activation
PKA    þ  d
T-cell infiltration
TK þ þ þ  
p38/MARK /þ   þ þ
ERK1/2 þ ? ?  
JNK1/2 þ ? ?  
NF-kB þ þ þ  þ neuropeptides that could stimulate degranulation and release of
PKC isoforms þ (a, b, d, e, y, m) þ  ? þ (y) the protease tryptase, which could in turn enhance demyelin-
ERK, extracellular signal-regulated protein kinase; PKA, protein kinase A. ation and inflammation through stimulation of protease
*Extracellular. activated receptor-2 (PAR-2) (Fig. 1).
Affected brains in MS areas fill with fibrotic tissue forming the
MS plaque (109) that also contains activated mast cells (110–
attenuated and delayed in these mice (103). Subsequent studies 112). Gene array analysis of MS plaques showed overexpression
suggested that the inability of mast-cell-deficient mice to fully of genes for FceRI, the histamine-1 receptor, and tryptase, all of
develop EAE may also depend on reduced T-cell activation (104, which are associated with mast cells (113–115). Mast cell
105). Ig-free light chains can sensitize mast cell release of tryptase is increased in the cerebrospinal fluid (CSF) of patients
cytokines that induce T-cell-mediated immune reactions critical with MS (116), can activate peripheral mononuclear cells to
in MS (20). Mast cell contact with activated T cells leads to secrete TNF and IL-6 (117), and stimulate PARs that can lead to
secretion of matrix metalloproteinase-9 and IL-6 from human microvascular leakage and widespread inflammation (118–121).
mast cells (106). Moreover, mast cells can promote IgE- BBB breakdown (122) precedes any pathological or clinical
dependent and T-cell-independent proliferation and activation signs of MS (112, 123, 124), as shown by trans-BBB leakage of
through TNF-a release (107). We recently showed that mast albumin (125) and magnetic resonance imaging-gadolinium
cell contact with activated T cells stimulates the latter to produce studies (124). Mast cells have been proposed as the ‘immune
30-fold more IL-2, which is further increased when mast cells gate to the brain’ (126). They line the BBB (77) and are
are activated by MBP (108). activated in EAE, but they show ultrastructural signs of
Mast cells could, therefore, participate in the pathogenesis of activation without typical degranulation (127) (Fig. 2). Mast
MS in different ways (Table 6). They could be activated by cells migrate from the meninges (128) and from blood to brain
bacterial or viral antigens and release cytokines/chemokines, (129). Mast-cell-derived products can enter neurons, a process
selectively inducing T-cell/macrophage recruitment and acti- termed transgranulation, indicating a novel form of brain–
vation. Myelin damage could then release fragments and other immune system communication (130). Brain mast cells could
be activated by non-allergic stimulation, such as myelin basic
protein (MBP) (100), as well as by acute stress (131). Restraint
Table 5. Secretion-related genes upregulated during CRH activation
of HMC-1 cells* stress activated brain mast cells and led to CSF elevation of rat
mast cell protease I (132), effects abolished by polyclonal anti-
Code Gene name Fold increase
serum to CRH (132) and the CRH receptor-1 (CRHR1)
SPIR-1 Spir-1 protein 23.60 antagonist antalarmin (132, 133). Acute stress also increased
CDC42BPB CDC42-binding protein kinase b 12.65
(DMPK-like) BBB permeability through the action of CRH (134) on brain
PCANAP7 Synaptotagmin VII 7.20 mast cells (134, 135). Acute restraint stress also shortened the
MTMR7 Myotubularin-related protein 7 5.15
SYNGR2 Synaptogyrin 2 4.70 time required for the development of EAE in mice and increased
STX18 Syntaxin 18 2.34 BBB permeability (136). CRH/ mice with EAE were shown
SYP Synaptophysin 2.30
PCLO Piccolo 1.93 recently to have decreased clinical disability and decreased brain
RAB3A RAB3A, RAS oncogene family member 1.80 infiltration by immune cells (137). Restraint stress was also
STX1B2 Syntaxin 1B2 1.76
STXBP6 Syntaxin-binding protein 6 (amisyn) 1.70 reported to increase mortality rates and lead to higher central
nervous system viral load during Theiler’s virus infection (138).
*Our unpublished results. DMPK, dystrophy protein kinase.
Stressed mice had increased inflammatory lesions in spinal cord

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and developed autoimmune antibodies to MBP (139). Acute results suggest that mast-cell-derived cytokines in response to
restraint stress (140) as well as CRH (141) and its structurally stress, or other triggers, may be involved in MS exacerbations.
related peptide, urocortin (142), can activate mast cells and
induce mast-cell-dependent vascular permeability in rodent as
Inhibition
well as in human skin (143), another neuroectodermal tissue.
We recently showed that human mast cells express CRHR, There is still no curative therapy for MS (157). Mast cells were
activation of which leads to selective release of VEGF (144). The considered a therapeutic target for MS (158). Unfortunately,
frequency, chronicity, severity, and timing of stressors appear very few clinically available drugs can inhibit mast cell secretion.
to be important (145). Disodium cromoglycate (cromolyn) was originally shown to
The effect of stress and CRH on mast cell activation and BBB inhibit rodent mast cells (159, 160), but it has proven
permeability may help explain clinical findings in patients with ineffective in human mast cells (161). Chondroitin sulfate,
MS. The symptoms of MS and the appearance of new lesions the major constituent of mast cell granules (161), and the
have been repeatedly shown to be precipitated by psychological flavonoid quercetin (162, 163) are potent mast cell inhibitors.
stress (109, 146–151). In one study in Denmark (151), parents Moreover, quercetin is the only compound shown to inhibit
who had unexpectedly lost a young child had a significantly differential release of IL-6 in response to IL-1 by reducing
increased risk of MS compared with other bereaved parents. intracellular calcium ions and PKCy phosphorylation (89).
Meta-analysis of 14 prospective studies showed a significantly Flavonoids may also inhibit mast cell degranulation through
increased risk of MS exacerbations after stressful events (152). inhibition of the intracellular activation of Syk (164).
The role of ‘stress-response systems for the pathogenesis and Flavonoids may also be acting as a 78-kDa protein (165)
progression of MS’ was reviewed recently, and it was proposed shown to mediate the inhibitory effect of cromolyn on rat mast
that MS is associated with glucocorticoid-insensitive immune cells (160) and found to be homologous to moesin (166). The
cells (153). Such a finding has never been documented. An inhibitory receptor IRp60 (CD300a) was shown to be expressed
experimental study argued that stress does not affect MS because in human cord blood mast cells, and its neutralization in mice
the function of peripheral blood leukocytes in patients with MS led to increased mediators (167). Human mast cells also express
is apparently unaffected by stress (154). However, this the myeloid cell inhibitory receptor CD200, engagement of
reasoning is faulty, as stress may predominantly affect mast which inhibited FceRI-induced phosphorylation activation
cells and T cells but not peripheral leukocytes. In fact, restraint (168). Two peptides derived from complement component
stress induced mast-cell-dependent increase in mouse serum IL- C3a, C3aþ, and C3a9 were shown to inhibit FceRI-induced
6 levels (155), while examination stress dramatically increased degranulation and TNF-a release (169). Degranulation in
serum TNF-a levels in medical student volunteers (156). These response to FceRI aggregation or compound 48/80 was

Fig. 3. Summary scheme showing morphological

appearances at the ultrastructural level of rat
peritoneal mast cells, along with potential triggers
and proposed pathophysiologic functions. Intact
(center), exocytotic degranulation (left), and intra-
granular changes (right).

72 Immunological Reviews 217/2007

 Theoharides et al
Mast cell mediator release in inflammation

severely impaired in IL-2-inducible T-cell kinase-1 mice (170). mast cells, especially in the brain, must utilize the mast cell’s
Nitric oxide also blocked FceRI-induced IL-4 and IL-6 pro- ability to secrete specific mediators selectively without
duction through TNF-a inhibition of Jun (171). degranulation. Differential or selective release of mast cell
It is of interest that flavonoids known to inhibit mast cell mediators without degranulation has been stressed repeatedly
secretion have also been shown to inhibit macrophage myelin as critical in the pathogenesis of inflammatory diseases (15,
phagocytosis (172) and EAE (173, 174). The flavone luteolin 177), atopic dermatitis and psoriasis (178), chronic fatigue
was also a strong inhibitor of human autoimmune T cells (175), syndrome (179), cancer (26), coronary artery disease (177),
and we showed that luteolin can inhibit mast cell activation and fibromyalgia (180), inflammatory arthritis (181), interstitial
mast cell-dependent T-cell activation (108). cystitis (182, 183), migraines (184), and MS (15, 131, 158)
(Fig. 3). Understanding the mechanism of differential release
Conclusion
could permit us to selectively inhibit mast cell involvement in
Mast cells are unique immune cells that can be activated by pathological inflammatory conditions, while permitting their
numerous triggers, including CRH (176). The versatile roles of function in innate or acquired immunity.

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