Cytokines, Mart 2014

1
are Molecules that communicate among cells of the

immune system
In general,
cytokines are soluble molecules, although some also exist in
membrane-bound forms.
The interaction of a cytokine with its receptor on a target cell can
cause changes in the expression of adhesion molecules and
chemokine receptors on the target membrane,
thus allowing it to move from one location to another.
Cytokines can also signal an immune cell to increase or

decrease the activity of particular enzymes or to
change its transcriptional program,
thereby altering and enhancing its effector functions.
Finally,
they can instruct a cell when to survive and when to die.
cytokine all molecules that communicate among immune cells,

Chemokine is subpopulation of cytokines that share the specific
purpose of mobilizing immune cells from one organ, or indeed,
from one part of an organ, to another.
dulu monokin, limfokin, skrg cytokin karena banyak dapat menghasilkan cytokin misal fibroblas
Chemokines belong to the class of molecules called chemoattractants,

molecules that attract cells by influencing the assembly,
disassembly, and contractility of cytoskeleton proteins and the
expression of cell-surface adhesion molecules.
Chemokines attract cells with the appropriate chemokine receptors to
regions where the chemokine concentration is highest.
chemokine is used when referring to molecules that move

immune cells from place to place,
cytokine is employed when referring to any other messenger
molecule of the immune system.
3
Cytokines that act on cells some

distance away from the
secreting cell, such that they
must pass through the
bloodstream before reaching
their target, are referred to as
jauh ke
endocrine dibawa BV prgi
tempat lain
Those that act on cells near the secreting cell,

such that the cytokine merely has to diffuse a
few ngstroms through tissue fluids or across
an immunological synapse, are referred to as
paracrine. bekerja sel terdekat
Sometimes, a cell needs to receive a signal
through its own membrane receptors from a
cytokine that it, itself, has secreted. This type of
signaling is referred to as
autocrine.disekresi, balik kerja kes sel sendiri = kanker
inducernya apa aja? injury, patogen
An inducing stimulus, which

may be an antigen or
another cytokine, interacts
with a receptor on one cell,
inducing it to secrete cytokines
stimulasi sel menghasilkan sitokin
that in turn act on receptors of
a second cell, bringing
about a biological
pergi ke sel lain ,bisa meningkatkan / menurunkan aktivitas
consequence. sitokin bisa trigger
EFEK biologi
In the case of IL-2,

both cells may be antigenactivated T cells that secrete
IL-2, which acts both on
the secreting cell and on
neighboring, activated T cells.
bisa ke sel lain atau bisa balik ke diriya
FIGURE 4-2 Overview of the induction and
function of cytokines.
Cytokines
are low molecular weight, soluble proteins that are
produced in response to an antigen and function as
chemical messengers for regulating the innate and
adaptive
immune systems.
hanya diproduksi dgn adanya stimulus, produksinya terbatas! jika berlebihan meniimbulkan
penyakit
They are produced by virtually all cells involved in innate

and adaptive immunity, but especially by T helper (TH)
cell.
The activation of cytokine-producing cells triggers

them to synthesize and secrete their cytokines.
are able to bind to specific cytokine receptors on other cells
of the immune system and influence their activity in some
manner.
maria immaculata iwo, sf itb
Cytokines
activate and deactivate phagocytes and immune defense cells,
increase or decrease the functions of the different immune
defense cells,
promote or inhibit a variety of nonspecific body defenses.
For example,
TNF, INF, IL
inflammatory cytokines promote inflammation,

chemokines allow leukocytes to adhere to the inner wall of
capillaries, squeeze out into the surrounding tissue, and be
attracted to the infection site,
type-I interferons prevent viral replication within infected

host cells.
Cytokines are pleiotropic, redundant, and

multifunctional
Pleiotropic
IL4 ke B Tc Mast cell
means that a particular

cytokine can act on a
number of different
types of cells rather
than a single cell type.
Redundant
IL 2 4 5 ke B
refers to the ability of a

number of different
cytokines to carry out
the same function.
Multifunctional
means the same
cytokine is able to
regulate a number of
different functions.
INF gamma pny perasn

aktivasi M.fag
There are three functional categories of

cytokines:
1. Regulate innate immune responses,
2. Regulate adaptive Immune responses,
3. Stimulate hematopoiesis
faktor penstimulasi koloni, EPO, colony stimulating factpr
Cytokine Network
Many cytokines have effects on many cells and organ systems
in addition to functions in immune systems
Referred to as the cytokine network
maria immaculata iwo, sf itb 10
11
Cytokine Antagonists
aktivitas sitokin dgn cara apa?
These proteins act in one of two ways:

- they bind directly to a cytokine receptor but fail to
activate the cell, thus blocking the active cytokine from
binding, or berikatan langsung ke reseptor
- they bind directly to the cytokine itself, inhibiting its ability to
bind to the cognate receptor. berikatan lsg ke sitokinnya sendiri
The IL-1 Receptor Antagonist Blocks the IL-1 cytokine Receptor
Cytokine Antagonists Can Be Derived from Cleavage of the
cytokine Receptor menghambat aktivitas sitokin
12
General Properties of Cytokines and

Chemokines
1. Cytokines Mediate the Activation, Proliferation, and Differentiation of
Target Cells contoh prolliferasi dan diferensiasi: pada sel B teraktivasi Th

dengan IL 4
2. Cytokines Have Numerous Biological Functions

3. Cytokines Can Elicit and Support the Activation of Specific
T- Cell Subpopulations
4. Cell Activation May Alter the Expression of Receptors and

Adhesion Molecules
molekul adhesi (menempel)
5. Cytokines Are Concentrated Between Secreting and Target Cells

(target selnya yg parakrin atau autokrin)
6. Signaling Through Multiple Receptors Can Fine Tune a Cellular

Response sitokin bisa bekerja pada reseptornya PADA PERMUKAAN SEL
IMUN KITA
13
Antigen
CD40
MHC II
B
cell
Cytokine
receptor
T helper
cell
cell
1. Antigen presentation
to Th cell
TCR
CD28
2. B7 expressed
Immunoglobulin
receptor
slain mol pengenal permukaan

4. Cytokine binds
dia juga punya sitokin res.jadi kira2 apa bedajjj
to cytokine
receptor, CD40
ligand binds to
CD40
3. Th cell is
activated and
expresses CD40
ligand, cytokines
secreted
CD40
ligand
cell
cell
cell
B
5. B cell activated
6. B cells proliferate, differentiate, secrete Ig
cell
T helper
cell
14
Cytokine
Th cell
Class II MHC
APC
Th cell
B cell
B cell takes up and
presents antigen
Th cells are primed by antigenpresenting cell

Th cell
Th cell
B cell
B-T cell cooperation
B cells receive signals from T cells
B cell
B cell
Antibody forming
cell
B cell
Antibody forming
cell
B cell
B cells divide
B cell
Antibody forming
cell
B cell
B
memory
cell
15
Cytokines
Is Non-antibody proteins acting as mediators
between cells (Communicator molecule)
jadi kira2 apa bedanay Cy dgn Ab, Ab spesifik berikatan dgn epitop, Cy tidak
termed:
Monokines
mononuclear phagocytes
Lymphokines
istilah ini sudah tidak ada lagi
activated T cells, especially helper T cells
Properties of Cytokines
1.
Produced by cells involved in both natural and specific

immunity
2.
Mediate and regulate immune responses
3.
Are non antigen-specific glycoprotein
4.
Generally synthesized and rapidly secreted in response to a

stimulus
5.
Secretion brief and limited

- not stored within the cell that makes them
- have very short half-lives
High level of
TNF- secreted
- cytokines produced as needed
by macrophage
- function occurs in a burst
lead to
septic shock
17
6. Can be produced by many cell types and act on many cell

types (pleiotropic)
7. each binding to its own cell-surface receptor
(IL, TNF, hematopoietin, chemokines family receptors)
8. one cytokine may affect the action of another can be additive, synergistic or antagonistic effect on the
target cell
enhance or suppress production of other cytokines
exert positive or negative regulatory mechanisms for
immune responses
9. Can have similar actions (redundant)
IL-6 and IL-1 induce fever
19
IL
Hematopoietic
TNF
Chemokines
IL2 R
IL-4
IL4 R
IL2 R
IL9 R
IL-9
IL2 R
IL7 R
IL-7
?
IL2 R
IL2 R
IL-15
IL15 R
IL2 R
IL2 R
IL2 R
Receptor for: IL-2
A defect in the common IL-2R chain was been shown to cause a

profound immune deficiency in boys: the activatory effects of
multiple cytokines were inhibited by this defect
20
Soluble (glyco-)proteins mediating

interactions between immune cells
Cytokines
Active at low concentrations

Pleiotropic, Redundancy, synergy and
antagonism
Paracrine/autocrine activity
Overlapping activities
Specific receptors
Cytokine network
are a crucial link between cells of the immune

system and other systems in the body
IL-2 acts on T cells as well as on osteoclast
TGF- acts on T & B cells, connective tissue
fibroblasts
21
22
23
maria immaculata iwo, sf 24

itb
25
maria immaculata iwo, sf 26

itb
Mediators and Regulators of

Natural Immunity
Tumor Necrosis Factor-alpha (TNF-)

Interleukin-1 (IL-1)
Chemokines (Chemotactic cytokines)
Type I Interferons (IFN- and IFN-)
anda bisa baca sendiri
Tumor Necrosis Factor (TNF-)

Produced by activated macrophages
Most important mediator of acute inflammation in
response to microbes, especially Gram-negative
bacteria (LPS)
Mediates recruitment of neutrophils and
macrophages to site of inflammation
Acts on hypothalamus to produce fever
Promotes production of acute phase proteins
Cytokines and their function

Interleukins (abbreviated IL with a number, IL-1 IL15)
Tumor necrosis factor (TNF , )

Transforming Growth factors (TGF , , and )
Interferon (IFN , , and )
Colony-stimulating factors
(GM-CSF, G-CSF, M-CSF)
sitokin ada yg stimulasi dan supres
immunostimulatory
immunosupressive
Inhibition of
T-cell signaling
Activation of APCs
- MHC
- Adhesion molecules
baca aja
Macrophage
Activation of endothelial cells
Apoptosis
Endothelial cells
Shock
NOS
Activation of neutrophils
TNF
O2
Lymphopaenia
Suppression
Of proliferation
Inhibition of DCs
Defective
Co-stimulation
Dendritic cell
Leukotriena
Cytokine induction
Cytokine induction
IL-6
IL-10
IL-6
Acute-phase response
IL-1
fever
TGF-
30
baca sendiri fungsi masinn2

sitokin
IL-1 function similarly to TNF in that it mediates acute inflammatory

responses.
It also works synergistically with TNF to enhance inflammation.
Functions of IL-1 include
promoting inflammation;
activating the coagulation pathway,
stimulating the liver to produce acute phase proteins,
catabolism of fat for energy conversion, inducing fever and sleep;
stimulates the synthesis of collagen and collagenase for scar
tissue formation;
stimulates the synthesis of adhesion factors on endothelial cells
and leukocytes for diapedesis;
activates macrophages.
IL-1 is produced primarily by monocytes, macrophages, dendritic cells,
endothelial cells, and some epithelial cell.
Produced by activated macrophages,
monocytes
Effects similar to those of TNF-
Produces fever, stimulate acute-phase

protein synthesis
Promotes proliferation of Th2 CD4+ T cells
Chemokines
Produced by many different leukocytes and
tissue cells
Large family of >50 substances
Recruit leukocytes to sites of infection
Play a role in lymphocyte trafficking
chemokines are low molecular weigh proteins that
play important roles in the inflammatory
response by inducing leukocyte populations to
migrate into area of infection
The chemokines include: IL-8,
Type I Interferons (IFN- and )

IFN- a family of many proteins produced by
macrophages,
IFN- a single protein produced by many cells
Both IFNs inhibit viral replication
Both increase expression of class I MHC
Both activate NK cells
Produced by activated macrophages and dendritic
cells
Stimulates production of IFN-
Induces differentiation of Th cells to become Th1 cells
Enhances cytolytic functions of cytotoxic T cells and
NK cells
Produced by activated macrophages, Th2 cells
An inhibitory cytokine
Inhibit production of Th1 CD4+ and macrophage function
Inhibits cytokine production by activated

macrophages
Inhibits expression of class II MHC and co-stimulatory

molecules on macrophages
36
Mediators and Regulators of

Specific Immunity
Interferon-gamma (IFN-)
Produced by Th>>Tc
Main growth factor for T cells
T cell
B cell
Monocyte
IL-2
secretion
Activation
NK
Stimulation
of division
T cell
Stimulation
of division and IFN gamma
release (and other
mediators)
Increase in NK
38
Cell activity
skip kesini
Autocrine Function of IL-2
Resting
T cell
Activated
T cell
Class II MHC
APC
T cell
intinya yg tadi kembali

menginduksi dirinya sendiri
IL2
IL4
IL7
Binds to IL-2 receptor
Division
T cell
T cell
T cell
T cell
T cell
T cell
Receptor
decay
T cell
T cell
39
IL-12 is a primary mediator of early innate immune responses to
intracellular microbes. It is also an inducer of cell-mediated
immunity.
It functions to
stimulate the synthesis of interferon-gamma by T-lymphocytes
and NK cells;
increases the killing activity of cytotoxic T-lymphocytes and NK
cells;
stimulates the differentiation of naive T4-lymphocytes into
interferon-gamma producing Th1 cells.
It is produced mainly by macrophages and dendritic cells.
Produced by Th2 cells and mast cells
Growth factor for B and Th2 CD4+ cells
Promotes IgE and IgG synthesis
Inhibits Th1 CD4+ T cells
Stimulates development of Th2 cells from nave Th
cells
Promotes growth of differentiated Th2 cells
Produced by Th2 cells
Promotes growth and differentiation of
eosinophils
Activates mature eosinophils

IL-4 and IL-5 can work together
Helminths opsonized with IgE can be killed by
activated eosinophils
Produced by activated macrophages, Th2 cells
Inhibits production of IFN- by Th1 cells needed to
activate macrophages
43
gamma = modulator
Interferon-gamma (IFN-)
Produced by Th cells >> Tc and NK cells
Numerous functions in both natural and specific
immunity
Th1 cell >
Tc cell
NK
Granulocyte
Activation
Macrophage
Activation
Many cell
types
Weak anti-viral activity,

Stops cell division,
Stops hematopoiesis
Activation
IFN
secretion
T cell
T cell activation
Endothelial cell
NK
B cell
Increase in
NK cell
activity
Many cell
types
Differentiation, Induction of class I

Stops cell division and class II MHC
44
Stimulators of Hematopoiesis
Colony-Stimulating Factors (CSF)
Granulocyte-macrophage CSF (GM-CSF)
promotes growth and differentiation of bone
marrow progenitors
Macrophage CSF (M-CSF) is involved in
development and function of monocytes and
macrophages
Granulocyte CSF (G-CSF) stimulates production
of polymorphonuclear leucocytes (PMN)
Cytokines Regulate Ig Class Switching

Fc region of antibodies determines effector
function in different anatomical locations
Class (isotype) switching produces class or
subclass of antibody most effective in host
defense
Cytokines acting alone or in combination
regulate class switching
Effects on Cells of Immune System

B cell
Proliferation,
Differentiation,
Ig secretion
and selection
IL-1
IL-2
IL-4
IL-5
IL-6
IFN
T cell
Proliferation,
Differentiation,
Cytokine
production
Lymphocyte
NK
Activation of cells of
immune system
cytokines
LAK
Cytokine production
Macrophage
47
Cytokine Effects on Organ Systems
Hypothalmus
Fever
Pituitary
ACTH
Lymphocyte
cytokines
Macrophage
Adrenal
gland
Corticosteroid
Liver
Acute phase proteins
Cytokine Effects on Various Cells

IL1 TNF IFN
IFN IFN
Fibroblasts
Fibrogenesis
Extracellular
matrix
Lymphocyte
cytokines
Macrophage
Many cell types
cytokines
IL1 TNF
Anti-viral state
Endothelial cell
Endothelial cells
Fibrinogen
Permeability change
adhesion
cytokines
Bone marrow
Hematopoiesis
Tissue remodeling
Tissue repair
Angiogenesis
Fibroblast
Extracellular
Matrix Osteoclasts
49
Systemic cytokines from liver into circulation

Pro inflammatory Cytokines Anti inflammatory cytokines
Tumor Necrosis Factor (TNF)

Interleukin-1ra (IL-1ra)
Transforming growth factor-
50
The various anti-cytokine strategies used by viruses:

The generation of viral products that interfere with cytokine
secretion yang virus lebih pintar, imun escape
The generation of cytokine homologs that compete with
natural cytokines or inhibit anti-viral responses
The production of soluble cytokine-binding proteins
bisa menghasilkan protein yg mengikat sitokin
The expression of homologs of cytokine receptors
The generation of viral products that interfere with

intracellular signaling
The induction of cytokine inhibitors in the host cell
51
53
The cytokine imbalance induces

mengapa org bisa mengalami ketidak seimbangan sekresi Cy
abnormal body temperature,

alterations in the respiratory rate,
and high white blood cell counts,
followed by capillary leakage, tissue injury,
widespread blood clotting, and
lethal organ failure.
Bacterial septic shock often develops because bacterial cell wall endotoxins
bind to innate immune system pathogen receptors, such as Toll-like
receptors on dendritic cells and macrophages, causing them to produce IL-1
and TNF- at levels that lead to pathological capillary permeability and loss
of blood pressure ditangani dengan antibody monoclonal anti TNF- or
IL-1
54
Cytokines based diseases

e.g.,
people with a defective receptor for IFN- are susceptible to
mycobacterial infections that rarely occur in the general population
Septic Shock Is Relatively Common and Potentially Lethal
Bacterial septic shock is one of the conditions that falls
under the general heading of sepsis.
Sepsis, in turn, may be caused not only by bacterial infection but
also by trauma, injury, ischemia (decrease in blood supply to
an organ or a tissue), and certain cancers.
Sepsis is the most common cause of death in U.S. hospital
intensive-care units and the 13th leading cause of death in
the United States.
A common feature of sepsis, whatever the underlying cause, is an
overwhelming production of pro-inflammatory and feverinducing cytokines such as TNF- and IL-1.
55
Bacterial Toxic Shock Is Caused by Superantigen

Induction of T-Cell cytokine Secretion
The TSST1 induce extremely high levels of TNF- and IL-1.
As in bacterial septic shock, these elevated concentrations of
cytokines can induce systemic reactions that include fever,
widespread blood clotting, and shock.
toxic shock syndrome toxin (TSST1) from

- Staphylococcus aureus;
- pyrogenic exotoxins from Streptococcus pyrogenes;
- Mycoplasma arthritidis supernatant (MAS)
56
Cytokine Activity Is Implicated in Lymphoid and Myeloid Cancers
Abnormalities in the production of cytokines or their receptors have been

associated with some types of cancer.
abnormally high levels of IL-6 are secreted by cardiac myxoma (a
benign heart tumor), myeloma and plasmacytoma cells, as well as
cervical and bladder cancer cells.
In myeloma and plasmacytoma cells,

IL-6 appears to operate in an autocrine manner
to stimulate cell proliferation.
57

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1

are Molecules that communicate among cells of the

thus allowing it to move from one location to another.

Cytokines can also signal an immune cell to increase or

cytokine all molecules that communicate among immune cells,

Chemokines belong to the class of molecules called chemoattractants,

chemokine is used when referring to molecules that move

Cytokines that act on cells some

Those that act on cells near the secreting cell,

inducernya apa aja? injury, patogen

An inducing stimulus, which

In the case of IL-2,

FIGURE 4-2 Overview of the induction and

They are produced by virtually all cells involved in innate

The activation of cytokine-producing cells triggers

inflammatory cytokines promote inflammation,

type-I interferons prevent viral replication within infected

Cytokines are pleiotropic, redundant, and

IL4 ke B Tc Mast cell

means that a particular

refers to the ability of a

INF gamma pny perasn

There are three functional categories of

maria immaculata iwo, sf itb 10

maria immaculata iwo, sf itb

These proteins act in one of two ways:

General Properties of Cytokines and

Target Cells contoh prolliferasi dan diferensiasi: pada sel B teraktivasi Th

2. Cytokines Have Numerous Biological Functions

4. Cell Activation May Alter the Expression of Receptors and

molekul adhesi (menempel)

5. Cytokines Are Concentrated Between Secreting and Target Cells

6. Signaling Through Multiple Receptors Can Fine Tune a Cellular

slain mol pengenal permukaan

6. B cells proliferate, differentiate, secrete Ig

Th cells are primed by antigenpresenting cell

B-T cell cooperation

B cells receive signals from T cells

istilah ini sudah tidak ada lagi

activated T cells, especially helper T cells

maria immaculata iwo, sf itb 16

Produced by cells involved in both natural and specific

Mediate and regulate immune responses

Are non antigen-specific glycoprotein

Generally synthesized and rapidly secreted in response to a

Secretion brief and limited

6. Can be produced by many cell types and act on many cell

Receptor for: IL-2

A defect in the common IL-2R chain was been shown to cause a

Soluble (glyco-)proteins mediating

Active at low concentrations

are a crucial link between cells of the immune

maria immaculata iwo, sf itb

maria immaculata iwo, sf itb

maria immaculata iwo, sf 24

maria immaculata iwo, sf 26

Mediators and Regulators of

Tumor Necrosis Factor-alpha (TNF-)

anda bisa baca sendiri

Tumor Necrosis Factor (TNF-)