Maria Immaculata Iwo

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 Characteristic of cytokine
 Molecules that communicate among cells of the immune
system are referred to as cytokines.
 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.
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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.

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.

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 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
endocrine
Those that act on cells near the secreting cell,
such that the cytokine merely has to diffuse a
few Ångstroms through tissue fluids or across
an immunological synapse, are referred to as
paracrine.
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.

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 An inducing stimulus, which
may be an antigen or
another cytokine, interacts
with a receptor on one cell,
inducing it to
secrete cytokines that in turn
act on receptors of a second
cell, bringing
about a biological
consequence.

In the case of IL-2,

both cells may be antigen-
activated T cells that secrete
IL-2, which acts both on
the secreting cell and on
neighboring, activated T cells.
FIGURE 4-2 Overview of the induction and
function of cytokines. 5
 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.
• 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.
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• 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,
– 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.

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 Cytokines are pleiotropic, redundant, and
multifunctional
 Pleiotropic
– means that a particular
cytokine can act on a
number of different
types of cells rather than
a single cell type.
• Redundant
– 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.
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Cytokine Antagonists

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

- they bind directly to the cytokine itself, inhibiting its

ability to bind to the cognate receptor.

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Three functional categories of cytokines:
1. Regulate innate immune responses,
2. Regulate adaptive Immune responses,
3. Stimulate hematopoiesis

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”

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 General Properties of Cytokines and
Chemokines
1. Cytokines Mediate the Activation, Proliferation, and Differentiation of
Target Cells

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

5. Cytokines Are Concentrated Between Secreting and Target Cells

6. Signaling Through Multiple Receptors Can Fine Tune a Cellular

Response
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 Antigen

CD40
B T helper TCR
B MHC II cell cell
cell
1. Antigen presentation
CD28
to Th cell
Cytokine Immunoglobulin 2. B7 expressed
receptor 3. Th cell is
receptor
activated and
4. Cytokine binds expresses CD40
to cytokine ligand, cytokines
receptor, CD40 secreted
ligand binds to
CD40
CD40
ligand
B B B
cell cell cell B T helper
cell cell
5. B cell activated

6. B cells proliferate, differentiate, secrete Ig Cytokine

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 Class II MHC
Th cell APC Th cell B cell

Th cells are primed by antigen- B cell takes up and

presenting cell presents antigen

Th cell Th cell
B cell
B-T cell cooperation
B cells receive signals from T cells

B cell B cell B cells divide

B cell B cell B cell B cell

Antibody forming Antibody Antibody B memory

cell forming forming cell
cell cell 17
 Cytokines

Is Non-antibody proteins acting as mediators

between cells (Communicator molecule)

termed:
• Monokines
– mononuclear phagocytes
• Lymphokines
– activated T cells, especially helper T cells

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 Properties of Cytokines
1. Produced by cells involved in both natural and specific
immunity
2. Mediate and regulate immune responses
3. Are nonantigen-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
- cytokines produced as needed TNF-α secreted
by macrophage
- function occurs in a burst  lead to
septic shock
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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

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  IL
 Hematopoietic
 TNF
 Chemokines
Receptor for: IL-2 IL-15 IL-7 IL-9 IL-4

IL15 Rα
IL2 Rα
IL2 Rβ

IL2 Rβ
IL2 Rγ

IL2 Rγ

IL2 Rγ

IL2 Rγ

IL2 Rγ
IL7 R

IL9 R

IL4 R
?

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
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 Soluble (glyco-)proteins mediating Cytokines
interactions between immune cells
 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
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 Mediators and Regulators of
Natural Immunity

• Tumor Necrosis Factor-alpha (TNF-α)

• Interleukin-1 (IL-1)
• Chemokines (Chemotactic cytokines)
• Type I Interferons (IFN-α and IFN-β)
• Interleukin-12 (IL-12)
• Interleukin-10 (IL-10)

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 Tumor Necrosis Factor (TNF-α)

• 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

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 Cytokines and their function

• Interleukins (abbreviated IL with a number, IL-1 – IL15)

• Tumor necrosis factor (TNF α, )
• Transforming Growth factors (TGF α, , and  )
• Interferon (IFN α, , and )
• Colony-stimulating factors
(GM-CSF, G-CSF, M-CSF)

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 immunostimulatory immunosupressive
Activation of APCs Inhibition of
- MHC T-cell signaling
- Adhesion molecules
Macrophage

Activation of endothelial cells Apoptosis

Endothelial cells
Shock
NOS Lymphopaenia
Activation of neutrophils Suppression

O•2
TNF Of proliferation

Inhibition of DCs
Defective
Co-stimulation

Dendritic cell
Leukotriena

Cytokine induction Cytokine induction

IL-10 IL-6

IL-6 IL-1
TGF-ß
Acute-phase response fever 32
 Interleukin-1 (IL-1)
• 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.
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 Interleukin-1 (IL-1)
• Produced by activated macrophages,
monocytes
• Effects similar to those of TNF-α
• Produces fever, stimulate acute-phase
protein synthesis
• Promotes proliferation of Th2 CD4+ T cells

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 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,
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 Type I Interferons (IFN-α and β)

• IFN-α a family of many proteins produced by

macrophages,
• IFN-β a single protein produced by many cells
• Both IFNs inhibit viral replication
• Both increase expression of class I MHC
• Both activate NK cells

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 Interleukin-12 (IL-12)

• Produced by activated macrophages and dendritic

cells
• Stimulates production of IFN-γ
• Induces differentiation of Th cells to become Th1 cells
• Enhances cytolytic functions of cytotoxic T cells and
NK cells

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 Interleukin-10 (IL-10)

• 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

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 Mediators and Regulators of
Specific Immunity

• Interleukin-2 (IL-2)
• Interleukin-4 (IL-4)
• Interleukin-5 (IL-5)
• Interleukin-10 (IL-10)
• Interferon-gamma (IFN-γ)

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 Interleukin-2 (IL-2)
• Produced by Th>>Tc
• Main growth factor for T cells

T cell

Stimulation
B cell
of division
IL-2
Monocyte
secretion
T cell
Stimulation
Activation of division and IFN gamma
NK release (and other
Increase in NK mediators)
Cell activity 40
 Autocrine Function of IL-2

Class II MHC
APC
Resting Activated IL2
T cell T cell IL4 IL7

T cell Binds to IL-2 receptor

Division

T cell T cell T cell T cell

Receptor
decay

T cell T cell T cell T cell 41

 Interleukin-12 (IL-12)

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.

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 Interleukin-4 (IL-4)

• 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 naïve Th
cells
• Promotes growth of differentiated Th2 cells

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 Interleukin-5 (IL-5)

• 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

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 Interleukin-10 (IL-10)

• Produced by activated macrophages, Th2 cells

• Inhibits production of IFN-γ by Th1 cells needed to
activate macrophages

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 Interferon-gamma (IFN-γ)
• Produced by Th cells >> Tc and NK cells
• Numerous functions in both natural and specific
immunity

NK Th1 cell >

Tc cell
Granulocyte Endothelial cell

Activation
Activation IFN 
Increase in
secretion NK NK cell
Macrophage
activity
Activation
Many cell types Many cell types
T cell B cell
Weak anti-viral activity,
Differentiation, Induction of class I
Stops cell division, T cell activation
Stops cell division and class II MHC46
Stops hematopoiesis
 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)

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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

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 Effects on Cells of Immune System

B cell T cell
NK LAK
Proliferation,
Differentiation, Proliferation, Activation of cells of
Ig secretion Differentiation, immune system Cytokine production
and selection Cytokine
production

IL-1
IL-2
IL-4
IL-5
IL-6
IFN Lymphocyte cytokines Macrophage

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 Cytokine Effects on Organ Systems

Hypothalmus
Fever
Pituitary

ACTH
Lymphocyte Macrophage
cytokines
Adrenal
gland

Corticosteroid

Liver

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Acute phase proteins maria immaculata iwo, sf itb
 Cytokine Effects on Various Cells
IL1 TNF IFNα
Fibroblasts IFNβ IFNγ
Fibrogenesis
Extracellular
matrix Lymphocyte Macrophage
cytokines
Many cell types
cytokines
Anti-viral state

IL1 TNF
Endothelial cell

Endothelial cells Tissue remodeling

Bone marrow
Fibrinogen Tissue repair
Permeability change Hematopoiesis
adhesion Angiogenesis
Fibroblast
Extracellular
cytokines
Matrix Osteoclasts
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 Systemic cytokines from liver into circulation
• Pro – inflammatory Cytokines Anti – inflammatory cytokines
• Tumor Necrosis Factor (TNF) Interleukin-1ra (IL-1ra)
• Interleukin-1 (IL-1) Transforming growth factor- 
• Interleukin-1 (IL-1) Interleukin-10 (IL-10)
• Interleukin-6 (IL-6)
• Interleukin-8 (IL-8)

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The various anti-cytokine strategies used by
viruses:

• The generation of viral products that interfere with cytokine secretion

• The generation of cytokine homologs that compete with natural
cytokines or inhibit anti-viral responses
• The production of soluble cytokine-binding proteins
• 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
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