Cytokines

Ahmad Shihada SilmiHematologist & Immunologist

IUG

General Characteristics

• 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• (REDUNDANCY): different cytokines

may have the same effect.

General Characteristics

• 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– Hematopoiesis– Adaptive Immunity– Innate Immunity– Inflammation

• Activities Established Thru Recombinant Cytokines (Simplistic Approach), In Vivo Function Can Vary

General Functions1- Mediators of natural/innate

immunity • 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:

A. TNF ( tumor necrosis factor):

1) Causes endothelial cells to produce adhesion molecules for lymphocytes and secret chemokines ( guide leukocytes to the site of inflammation “chemotaxis “ ).

2) Causes fever.

B. IL-7: similar / same effect as TNF.C. IL-6D. IL-8E. INF-γ: causes activation of macrophage.

General FunctionII- MEDIATORS & REGULATORS OFADAPTIVE

IMMUNITY • 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:

• 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:

– 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-

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 ).

• How Does Immune Specificity Fit With Non-Specific 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

Cytokines Are Non-Specific

Cytokine Receptors

• 5 Major Families– 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 pro-inflammatory 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 CytokinesRegulation of Cytokines

• Chromatin Structure

(Regulation of expression)

Cytokine TherapiesSuppression of TH-cell poliferation and TC-cell activation