1. CYTOKINE Hendy Kusnadi Pradipa Syarif

2. What Is A Cytokine? A small protein released by cells that has a specific effect on the interactions between cells, on communications between cells or on the behavior of cells. They act via cell surface receptors to mediate and regulate the amplitude and duration of the immune-inflammatory responses, through activation of marcophages, controlling growth and differentiation of T and B cells. Divided into 3 terms: 1. Monokines – produced by mononuclear phagocytes 2. Lymphokines – produced by activated T cells, primarily helper T cells 3. Interleukins – name given to many cytokines, abbreviated as IL and given a number such as tumor necrosis factor (TNF) and the interferons (IFN), which trigger inflammation and respond to infections.

3. Cytokines Low molecular weight proteins (30 KDa) Bind receptors, alter gene expression Can bind the secreting cell (autocrine) Can bind another cell close by (paracrine) Few cases bind another cell far away (endocrine) Cytokines regulate immune responses Cytokines can activate many cells A cytokine can be pleiotropic (different effect on different cells) Synergism, redundancy, antagonism

5. General Characteristic Mediate and regulate the immune system Secretion is brief and self-limited Individual cytokines are produced by multiple cell types One cytokine can act on different cells (pleiotropic) Multiple cytokines may have the same functional effects (reduntant)

6. Functional Categories of Cytokines Cytokines classified according to their biologic actions into three groups: 1) Mediators and regulators of innate immunity - Produced by activated microphages and NK cells in response to microbial infection - they act mainly on endothelial cells and leukocytes to stimulate the early inflammatory response to microbes

7. Functional Categories of Cytokines 2) Mediators and regulators of acquired immunity - Produced mainly by T lymphocytes in response to specific recognition of foreign antigens - They include IL-2, IL-4, IL-5, IL-13, IFN, Transforming growth factor- β (TGF- β ) and lymphotoxin (TNF- β ) 3) Stimulators of haematopoiesis - Produced by bon marrow, stormal cells, leukocytes - Stimulate growth and differentiation of leukocytes - Stem cell factor, IL-3, IL-7, GM-CSF

8. Properties 1. Produced by cells involved in both natural and specific immunity 2. Mediate and regulate immune and inflammatory responses 3. Secretion brief and limited a. Cytokines are not stored as pre-formed molecules b. Synthesis initiated by new short-lived gene transcription c. mRNA short-lived d. Results in production of cytokines as needed

9. Properties 4. Many individual cytokines are produced by many cell types and act on many cell types (pleiotropic) 5. In many cases cytokines have similar actions (redundant). Redundancy is due to the following: Receptors for cytokines are heterodimers sometimes heterotrimers that can be grouped into families in which one subunit is common to all members of a given family. Since the subunit common to all members of the family functions in binding cytokine and in signal transduction, a receptor for one cytokine can often respond to another cytokine in the same family.

10. Properties 6. Often influence the synthesis of other cytokines a. Can produce cascades, or enhance or suppress production of other cytokines b. Exert positive or negative regulatory mechanism for immune and inflammatory responses 7. Often influence the action of other cytokines. Effects can be: a. antagonistic b. additive c. greater than additive (synergistic)

11. Properties 8. Bind to specific receptors on target cells with high affinity. Compare with antigen binding to antibody or peptide binding to a MHC molecule which both show much lower binding affinities. 9. Cells that can respond to a cytokine are: a. Same cell that secreted cytokine: autocrine b. A nearby cell: paracrine c. A distinct cell reached through the circulation: endocrine 10. Cellular responses to cytokines are generally slow (hours), require new mRNA and protein synthesis

12. Cytokine Categories 4 Categories ◦ TNF family ◦ Chemokine family ◦ Interferon family ◦ Hematopoietin family Hematopoietin family ◦ -helical structure prevalence ◦ Little or no  -sheet ◦ Ex. IL-2 and IL-4 ◦ Amino acid sequences vary considerably

13. Cells That Make Cytokines And Their Function A Variety Of Cells Are Capable Of Making Cytokines However The Biggest Producers: T H Cytokines Are Involved In ◦ Hematopoiesis ◦ Adaptive Immunity ◦ Innate Immunity ◦ Inflammation See Appendix For Complete List And Function Activities Established Thru Recombinant Cytokines (Simplistic Approach), In Vivo Function Can Vary

16. Interferons (IFNs) Interferons (IFNs): are proteins secreted in response to viral infections or other stimuli * They include: - INF- α produced by leucocytes  induced by virus infected cells - INF- β produced by fibroblasts  - INF- γ produced by NK cells,TH1 cells, CD8 T-cells

17. Interferons (IFNs) Action of IFN- γ : - Activate Macrophages - Increase expression of MHC-I and II on APCs - Enhance cytotoxic actions of Nk cells - Promote production of TH1 and inhibits proliferation of TH2

18. Cytokines 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

24. Receptor Signalling (IFN  R) Ligand Binds  Subunit Ligand Binding Causes Dimerization of Receptor JAKs Get Activated ◦ Phosphorylation of tyrosine residues on receptor ◦ Phosphorylation of JAKs themselves STATS Dock Receptor ◦ Phosphorylation of STATs by JAKs Dimerized STATs Translocate To Nucleus Gene Expression

26. Therapeutic Uses of Cytokines 1) Interferon in treatment of viral diseases, cancer 2) Several cytokines are used to enhance T-cell activation in immunofideficincy diseases, e.g. IL-2, IFN- ,TNF-  3) IL-2 and lymphokine activating killer cells (LAK) in treatment of cancer 4) GM-CSF induces increase in white cell count, it is used: a- To restore leukocytic count after cytotoxic chemotherapy induced neutropenia b- After bon marrow transplantation C- To correct AIDS-associated leukopenia

27. Therapeutic Uses of Cytokines 5) Anti-cytokines antibodies in management of autoimmune diseases and transplant rejection: a- Anti-TNF in treatment rheumatoid arthritis b- Anti-IL2R to reduce graft rejection 6) Anti-TNF antibodies in treating septic shock 7) Anti-IL-2R  in treating adult T-cell leukemia 8) Anti-IL-4 is under trial for treatment of allergies

28. THANK YOU Pradipa Syarif Hendy Kusnadi