Cytokines
Ahmad Shihada Silmi
Hematologist & Immunologist
IUG
General Characteristics
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Mediate and regulate the immune
system
Secretion is brief and self-limited
Individual cytokines are produced by
multiple cell types
Act of multiple cell types-pleiotrophic
(PLEITROPISM): one type of
cytokine may act on several different
cell types.
General Characteristics
Actions are redundant
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(REDUNDANCY): different cytokines may
have the same effect.
General Characteristics
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Effect synthesis and actions of other
cytokines.
(SYNERGY): two or more different
cytokines may have a greater than
additive effect.
(ANTAGONISM): one type of
cytokine may the action of another
type of cytokine.
Cells That Make Cytokines And
Their Function
• A Variety Of Cells Are Capable Of Making
Cytokines
• However The Biggest Producers: M and TH
• Cytokines Are Involved In
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Hematopoiesis
Adaptive Immunity
Innate Immunity
Inflammation
• Activities Established Thru Recombinant
Cytokines (Simplistic Approach), In Vivo
Function Can Vary
General Functions
1- Mediators of natural/innate immunity
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A.
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Produced mainly by mononuclear phagocytes in response to
infectious agents.
Act on endothelial cells ( production of adhesion molecules for
B-cells and T-cells to bind to and or leukocyte activation );
main members of this group are:
TNF ( tumor necrosis factor):
Causes endothelial cells to produce adhesion molecules for
lymphocytes and secret chemokines ( guide leukocytes to the site of
inflammation “chemotaxis “ ).
Causes fever.
B. IL-7: similar / same effect as TNF.
C. IL-6
D. IL-8
E. INF-γ: causes activation of macrophage.
General Function
II- MEDIATORS & REGULATORS OFADAPTIVE
IMMUNITY
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Produced mainly by T-lymphocytes in
response to specific regulation of antigen.
Act on lymphocyte to induce growth &
differentiation during the activation phase
at T-cell dependent immune response.
Also act on EFFECTOR CELLS (such as
mononuclear phagocytes, neutrophil and
eosinophils) in the effector phase of
adaptive immune response.
These are divided into:
A- ACTIVATORS OF CYTOTOXIC
RESPONSE:
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Induction of macrophage cytotoxic T cell & NK
cell activation.
Main members of the group:
– IL-2:causes exponential proliferation of T
cells after recognition of antigen
– IL-3
– INF-γ: similar effect to IL-2
– LT ( lymphotoxin): similar effect to TNF,
thus as a link between T-cell activation &
inflammation.
B- ACTIVATORS OF HUMORAL
RESPONSE:
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– Induction of B-cell activation
– Main members of the group:
IL-2: is produced by T-cells, thus have similar
gene effect on B-cells
IL-3
IL-4: similar/ same effect as IL-2, and also
cause isotype switch to IgE.
IL-5: causes isotype switch to IgA
IL-6: causes B-cells differentation to plasma
cells
TGF-B (Transforming Growth Factor- β):
causes isotype switch towards IgA
INF-γ: cause isotype switch towards IgG
General Function
III- Activators of inflammatory
cells
– Type II IFN
• IFN-g
General Functions
VI- Stimulators of hematopoiesis
• Produced by BONE MARROW STROMA CELL &
leukocyte to stimulate growth & differentation of
immature leukocytes.
• Main members of the group.
A. IL-3: causes induction of all principal hematocytes.
B. IL-7: induction of B- and T- lymphocytes.
C. CSF (STEM CELL FACTOR ) :induction of all principal
hematocytes.
D. GM-CSF (granulocyte –monocytes –CSF.
E. M-CSF (MONOCYTE-CSF ).
F. G-CSF (GRANULOCYTES-CSF ).
Cytokines Are Non-Specific
• How Does Immune Specificity Fit With NonSpecific Cytokines
• Answer 1: Thru Receptors
– Receptors Expressed On Antigen Activated Cells
• Answer 2: Close Proximity To Cytokine
Secreting Cells.
– Ex. APC-TH
– Cytokine Concentrations (TH) Are High Locally
– Only Interacting APC Gets Activated
• Answer 3: Short Half Life
– Short ½ Life Ensures Local Activity
Cytokine Receptors
• 5 Major Families
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Immunoglobulin Superfamily
Hematopoietin Receptor Family (Class I)
Interferon Receptor Family (Class II)
TNF Receptor Family
Chemokine Receptor Family
• Class I and II (Majority Of Receptors)
– Multimeric
– Upon Receptor Engagement, Tyrosine
Phosphorylation
Hematopoietin Receptor Family (Class I)
Th17 and Treg Cells
• Th17 (CD4+, FoxP3-)
– IL-17 is a proinflammatory cytokine
– Promotes secretion of
pro-inflammatory
cytokines (IL-6) from
fibroblasts, epithelial and
endothelial cells.
– Th17 cells are critical to
anti-bacterial immunity.
– Over expression of IL-17
is associated with
rheumatoid arthritis,
SLE, MS and asthma
• Treg (CD4+, Foxp3+)
– Natural (develop in
the thymus)
• Prevent effector T
cell development in LN
– Induced (develop in
the periphery)
• Develop under the
influence of TGF-ß
• Inhibit effector T cell
function in periphery.
Regulation of Cytokines
• Chromatin Structure
(Regulation of expression)
Cytokine Therapies
Suppression of TH-cell poliferation and TC-cell activation