1. Ahmad Shihada Silmi Hematologist & Immunologist IUG
Cytokines
Ahmad Shihada Silmi
Hematologist & Immunologist
IUG

2. 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.

4. General Characteristics
Actions are redundant
(REDUNDANCY): different cytokines may have the same effect.

5. 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.

9. 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

10. General Functions 1- 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:
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.

11. General Function II- 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:

12. 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.

13. 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

14. General Function III- Activators of inflammatory cells
Type II IFN
IFN-g

15. 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 ).

19. Cytokines Are Non-Specific
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

21. 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

22. Hematopoietin Receptor Family (Class I)

40. Th17 and Treg Cells Treg (CD4+, Foxp3+) 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.

42. Regulation of Cytokines
Chromatin Structure
(Regulation of expression)

43. Cytokine Therapies
Suppression of TH-cell poliferation and TC-cell activation