Understanding Cytokines in Immunology Lectures at Mu'tah University

1. Immunology/ Pharmacy Students • Cytokines and Chemokines • Lecture Dr. Mohammad Odibate Department of Microbiology and immunology Faculty of Medicine, Mu’tah University

2. Introduction to cytokines Definitions: • Cytokines: are small soluble proteins that regulate the immune system, orchestrating both innate immunity and the adaptive response to infection • Cytokines: modulate the functional activities of individual cells and tissues both under normal and pathologic conditions

3. Introduction to cytokines Cytokine Basics: Definitions: • Interleukins - produced exclusively by leukocyte • Lymphokines - produced by lymphocytes • Monokines - produced exclusively by monocytes • Interferons - involved in antiviral responses • Chemokines - promote chemotaxis. Cytokines behave like classical hormones in that they act at a systemic level, affecting • Inflammation • Septic shock • Acute phase reactions and • Wound healing

4. Introduction to cytokines Cytokine Activity: Cytokine actions may be characterized as: • Autocrine: self modulating • Paracrine :modulating cells in the immediate surroundings • Endocrine: affect distant cells • Retrocrine: modulating to stop host defense

5. Introduction to cytokines Cytokine Regulation: • Most Cytokines are not stored inside cells (exceptions are, for example TGF-β and Platelet-derived growth factor (PDGF) which are stored in platelets) • The expression of most cytokines is strictly regulated. • Expression is normally transient. • Cytokines are important positive or negative regulators of mitosis, differentiation, migration, cell survival, apoptosis, and transformation.

6. Cytokines of the innate and adaptive immunity DC Innate Immunity • IL-1 • TNF- α • - IL-6 • - Chemokines • IFN-α • IFN-ß Cytokines Cytokines Naïve Th cell Naïve CD8 CTL Naïve T h cell NK Adaptive Immunity CD4 Th2 CD4 Th1 CD8 CTL Th1 Cytokines Th2 Cytokines CTL Cytokines B cell

7. Cytokines of the innate immunity TNF-α & IL-1: vasodilatation & permeability Liver Pyrogens TNF- α/IL-1 DC Staphylococcal infection

8. Cytokines of the innate immunity TNF-α & IL-1: • Are proinflammatory cytokines produced by monocytes and macrophages induced by the microbial pathogens, bacterial lipopolysaccharides • Cause vasodilatation and increased vasopermeability • They are pyrogens • Activation of phagocytes • Activation of hepatocyte production of acute phase proteins • Induction of vascular adhesion molecules (selectins). • Induces the production of colony stimulating factors in the bone marrow, thereby increasing the available number of phagocytic cells IL-6 act similar to IL-1

9. Cytokines of the innate immunity IFN-α & IFN-ß: • They are produced by dendritic cells • Were named because they interfere with viral replication and cell division • Activating NKs and enhances the expression of MHC class I proteins, thus increasing the recognition and killing of virus-infected cells. • They are active against certain malignancies and other inflammatory processes

10. Cytokines of the innate immunity IFN-α & IFN-ß:

11. Cytokines of the innate immunity Chemokines: Chemokines = Chemoattractant Cytokines • Promote recruitment and activation of leukocytes • Can be divided into subclasses by virtue of structural properties. • Examples: Lymphotactin, MCP-1, RANTES, IL-8

12. Cytokines of the adaptive immunity Th2 Cytokines: IL-2 IL-4 IL-5 Dendritic cell Ag complexed with MHC class 2

13. Cytokines of the adaptive immunity In the lymph node, dendritic cell Start presenting Ag from extracellular pathogens to naïve T cells until Finding one T cell with specific TCR For the displayed Ag Dendritic cell Clonal selection naïve T cell

14. Cytokines of the adaptive immunity The binding between TCR, MHC2 , and CD4 activated the Differentiation and proliferation of naïve T cell Into Th2 lymphocyte IL-1 IL-5 IL-4 IL-5 IL-4 Differentiation Clonal expansion naïve T cell IL-2 TH2 cell TH2 cell TH2 TH2 TH2

15. Cytokines of the adaptive immunity IL-2 • Originally called T-cell growth factor (TCGF) • Produced mainly by CD4+T-lymphocytes • Allows clonal expansion of activated T-lymphocytes • IL-2 important actions: • It can increase immunoglobulin synthesis and J-chain transcription • Proliferation in B cells (with IL-4) • potently augment the cytolytic activity of natural killer (NK) cells.

16. Cytokines of the adaptive immunity IL-4 IL-4R B cell IL-4 IL-4 IL-5 IL-5 IL-4 will activate B cell proliferation IL-5 B cell B cell B cell B cell Clonal expansion IL-5 will activate B cell differentiation into plasma cells TH2 TH2 TH2 TH2

17. Cytokines of the adaptive immunity IL-4 • IL-4 is the major B-cell growth factor • IL-4 promotes the production of IgG2 and IgE and, along with IL-5, drives the differentiation and activation of eosinophils in both allergic immune responses and the response to parasitic infections IL-5 Stimulates B cell growth and increases immunoglobulin secretion. It is also a key mediator in eosinophil activation

18. Anti-inflammatory Cytokines TGF-ß: • Produced by regulatory T cells (Treg) • An anti-inflammatory cytokine • It inhibits the activation of macrophage and T cells. • It blocks the production of IL-12 and IFN-γ. • TGF-ß typically inhibits proliferation of activated B-cells.

19. Anti-inflammatory Cytokines TGF-ß: Active B cell

20. Anti-inflammatory Cytokines IL-10: • IL-10 has anti-inflammatory and suppressive effects on Th1 Cells. • It is produced by monocytes, macrophages, CD8 T cells, and Th2 CD4 T cells. • It inhibits antigen presentation by macrophages and dendritic cells • One of the major effects of IL-10 is the inhibition of IFN- production via the suppression of IL-12 synthesis

21. Cytokines and anticytokine therapies Cytokine-inhibiting agents that disrupt the interaction between cytokines and their receptors An example is infliximab (Remicade), an antibody bind human TNF-α and blocks the activity of TNF- α in rheumatoid arthritis and Crohn’s disease

22. Cytokine Assays • The biological activities of cytokines can be measured by a variety of bioassays which may employ factor-dependent cell lines, or antibodies (ELISA) • RT-PCR quantitation of cytokines detects the presence of mRNA encoding specific cytokines