1. CYTOKINES

2. What are Cytokines?
A collection of polypeptides used for communications between cells
Play role similar to hormones (messengers of the endocrine system)
Hormones usually act at a distance
Cytokines act locally
Differ from growth factors that are produced constitutively, while cytokine production is carefully regulated
Play an important role in both innate and adaptive immunity

3. Cytokine Nomenclature
Interleukins (1-18)
Interferons (alpha,beta,gamma)
Others (common names)

4. Cytokine - Mediated Effects
Cell growth
Cell differentiation
Cell death
Induce non-responsiveness to other cytokines/cells
Induce responsiveness to other cytokines/cells
Induce secretion of other cytokines

5. How do cytokines tell cells what to do?
Produced by cells as part of normal cellular activity and/or the result of environmental trigger
Bind to receptors on cells
Trigger signal transduction pathways
Initiate synthesis of new proteins

6. Properties of Cytokines
Proteins
Low molecular weight
Bind to receptor on either cell which produced it or another cell
Receptor binding triggers a signal
Signal results in altered pattern of gene expression

7. Cytokines Can Act in Three Different Manners
Autocrine
Cytokine binds to receptor on cell that secreted it
Paracrine
Cytokine binds to receptors on near by cells
Endocrine
Cytokine binds cells in distant parts of the body

9. Cytokine Actions Pleiotropy Redundancy Synergy Antagonism
Act on more than one cell type (INFa/b)
Redundancy
More than one cytokine can do the same thing (IFNa/b and IFN)
Synergy
Two or more cytokines cooperate to produce an effect that is different or greater than the combined effect of the two cytokines when functioning separately (IL-12 and IL-8)
Antagonism
Two or more cytokines work against each other (IL-4 and IL-12)

13. How Can Non-specific cytokines act Specifically?
Only cells expressing receptors for specific cytokines can be activated by them
Many cytokines have very short half-lives
Only cells in close proximity will be activated
High concentrations of cytokines are needed for activation
May require cell-to cell contact

14. Cytokine Receptor Families
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

15. Cytokines Regulate the Immune Response
Cells with the appropriate receptors become activated
To differentiate
To express receptors which will make them receptive to other cytokines
To secrete other cytokines

16. Involvement of Cytokines in the Immune Response
Alert to infection.tumor/etc.
Recruit cells to site
Specify type of immune response
Immune effector phase
Immune down-regulation
Immune memory and resetting the system
Early mediators (IFNa/b)
Chemokines (MIP-1a)
Early & late mediators (IL-2, IFNg, IL-4, IL-5)
Down-regulators (IL-10, TNFg)
Maintenance of cytokines, etc. (GM-CSF, IL-3, IL-7, etc.)

17. Early Mediators Interferons a/b Induced by dsRNA, etc.
Induced by CD40/CD40L pathway
IFNs can induce more of themselves
Directly interferes with viral replication
Activation of T and NK cells

18. Chemokines Recruit to sites of infection MIP-1alpha (NK and T cells)
MIG, RANTES (CD4+T cells)
IL-8 (neutrophils)
Eotaxin (eosinophils)

19. Early Mediators IL-12, IL-15, 1l-18, IFN-g (from NK cells), IL-10
Proinflammatory mediators
Produced by cell associated with innate immunity (macrophages, NK, etc.)
Mediate direct effects
Promote inflammation
Shape downstream responses

20. Late Mediators IL-2, IL-4, IL-5, IFN-g, TNF, IL-6, IL-10
Produced by cells of the adaptive immune response (T and B cells)
Direct effects
More immunoregulatory functions

21. Down Regulators IL-10, IL-11, TGF-b
Inhibit proliferation, cytokine production
Produced by both innate and adaptive cells

22. Maintenance Cytokines
GM-CSF, IL-3, IL-7, IL-9, etc.
Induce cell differentiation, cell growth

23. Cytokine Cross-Regulation
In a a given immune response, either TH1 or TH2 response dominates
Cytokines of one response tend to down-regulate the other type of response
Example: TH1 cells secrete IFN-g, which inhibits proliferation of TH2 subset

24. Cytokine Therapies
Suppression of TH-cell proliferation and TC-cell activation