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Lecturer: Ge Jin, Ph.D., ge.jin@case, 3683791

Lecturer: Ge Jin, Ph.D., ge.jin@case.edu, 3683791. Learning Objectives: 1. describe basic properties of cytokines 2. describe how cytokines regulate immunity (e.g. increase or decrease MHC expression and T cell activation…) 3. cytokine and oral diseases.

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Lecturer: Ge Jin, Ph.D., ge.jin@case, 3683791

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  1. Lecturer: Ge Jin, Ph.D., ge.jin@case.edu, 3683791 Learning Objectives: 1. describe basic properties of cytokines 2. describe how cytokines regulate immunity (e.g. increase or decrease MHC expression and T cell activation…) 3. cytokine and oral diseases NOTE: you need to download the PowerPoint file to your computer to read notes. Slides containing research results from my lab will be added during the lecture.

  2. Body as Host: Immune Molecules Cytokines properties, categories, signaling, function

  3. Cytokines • small, secreted, non-antibody proteins • produced by cells involved in both innate & adaptive immunity • mediate and regulate immunity, inflammation, and hematopoiesis

  4. Cytokines • Lymphokine: made by activated lymphocytes, especially TH cells, e.g. IL-2 • Monokine: made by mononuclear phagocytes, e.g. Mig/CXCL9 • Chemokine: chemotactic activity, e.g. IL-8, CXCL12 • Interleukin: interaction between leukocytes IL-1, IL-8, IL-10, IL-13…… • named by activity: Tumor Necrosis Factor a (TNFa), Colony Stimulation Factor (CSF), Transforming Growth Factorb (TGFb)….

  5. Cytokines • grouped by structures into families • interferons (IFN): type I (IFNa and IFNb), type II (IFNg) • Interleukin: IL-1, IL-2 • chemokine: CXCL and CCL chemokines • TNFa: TNFa, FasL, CD40L… • hematopoietin: erythropoietin (EPO), colony- stimulation factors (CSF)

  6. Properties of Cytokines • produced in response to immune stimuli • -- not store pre-formed • -- synthesis: DNA mRNA  protein  secretion • -- slow cellular response • can act on the cells that produce them (autocrine action) • can act on nearby cells (paracrine action) • can act on distance cells (endocrine action)

  7. Properties of Cytokines • can be produced by many cell types and act on many cell types (pleiotropic) • different cytokines can have similar actions (redundant)

  8. -- share receptors -- defect in a unique cytokine have little effect -- defect in a share component (common receptor) can have profound effects e.g. IL-2Rg defect X- linked SCID (Severe Combined Immunodeficiency)

  9. Properties of Cytokines • can modulate synthesis of other cytokines - cascades: e.g. TNFa IL-1 IL-6, IL-8… -enhance or suppress production of other cytokines: positive or negative • influence the action of other cytokines - antagonistic - additive - synergistic • short half life, low plasma concentration, bind to receptor with high affinity

  10. Cytokine Receptors (grouped by structures into families) Immunoglobulin superfamily: IL1R, TLRs… leucine-rich repeats immunoglobulin domain cell membrane Toll-IL-1 Receptor domain (TIR) Toll-like receptors (TLRs) IL-1 receptor

  11. Cytokine Receptors TNFR family: TNFa, FasL, CD40L…

  12. Cytokine Receptors class I receptor family: hematopoietin family CNTF LIF/OSM IL-6 IL-11 GM-CSF IL-3 IL-5 IL-2 IL-15 IL-7 IL-9 IL-7R IL-9R IL-3R IL-5R IL-2Ra CNTFR IL-15Ra GM-CSFRa g g g g IL-2b b gp130 gp130 b IL-2b b gp130 gp130 cell membrane cell membrane GM-CSF: Granulocyte macrophage colony-stimulating factor IL: interleukin gp130: glycoprotein 130 (m.w. 130 kDa)

  13. Cytokine Receptors class II receptor family: Interferon a, b, and g IFNARI IFNgRb IFNAR2b cell membrane IFNAR2c IFNgRa type I IFN receptor type II IFN receptor type I IFN: IFNa and IFNb, type II: IFNg

  14. Cytokine Receptors chemokine receptor family: CCR1-5, CXCR1-4 NH3 cell membrane COOH binding of a ligand to the receptor

  15. Cytokine Receptors TGFb receptors TGFb receptors have intrinsic kinase activity when interacting with ligands.

  16. Cytokine Signaling cytokines membrane receptors phosphorylation cascades transcription, Ca++… binding signal transduction activation

  17. Cytokine Signaling • NFkB signaling pathways • JAK/STAT signaling pathways • Chemokine signaling pathways • Cross-talk between pathways

  18. NFkB Signaling • Nuclear Factor kB (NFkB): • dimeric transcription factors: p65/RelA, c-Rel, RelB, p105/p50, p100/p52 • sequestered by inhibitory IkB proteins and retained in cytosol in resting cells • NFkB signaling inducers: • cytokines: IL-1, TNFa,… • microbial cell components: Fn cell wall, lipopolysacchrides (LPS),… • virus: retroviruses, double-stranded RNA (dsRNA),… • Receptors: • IL-1 receptors • Toll-like receptors (TLRs, innate immunity) • TNFa receptors

  19. IL-1 NFkB NFkB NFkB complex I complex II degradation IKK activation TAK1 activation IKKb IKKa IRAK4 IRAK IRAK4 IRAK IRAK4 IRAK IRAK complex III IkB IkB IkB IkB NFkB activation nuclear translocation MyD88 NEMO pellino1 pellino1 TRAF6 TRAF6 TRAF6 TRAF6 TAK1 TAK1 TAK1 Tollip TAB3 TAB1 TAB3 TAB1 TAB2 TAB2 innate & adaptive immunity TF ubiquitination& degradation IL-6 IL-8 hBD-2 …. u u u u u u u u u u p p p p p p p p p p p p p p p p p p p p p p Ubc13/Uev1A cell membrane IL-1 receptor nucleus TF phosphorylation ubiquitination

  20. NFkB Signaling Alternative NFkB activation pathways of immunity CD40L, LT-B, BAFF CD4/TCR UV-light p38-CKII PKC NIK IkB degradation NFkB activation

  21. JAK/STAT Signaling Pathway • JAK(Janus Kinases): a family of tyrosine kinases, JAK1-3, Tyk2 • STAT(Signal Transducers and Activators ofTranscription): transcription factors, STAT1-6,… • Cytokines: IFNa/b, IFN-g, Epo, GM-CSF, IL-6, IL-13… • in resting cells, non-phosphorylated, monomeric STATs reside in cytosol

  22. SJ Baker et al, Oncogene (2007) 26, 6724–6737.

  23. phospho- phospho- Receptor JAKs STATs binding Receptor JAKs IFNa/b IFNg receptor translocation binding target gene transcription STAT dimers DNA nucleus cdc25a, cyclin D1~3, c-myc, cyclin E, MMP9 p21, caspase 3, 1, 8…

  24. Chemokine Signaling • 2 major families: the CCL family and CXCL family • CCL1~27, CXCL1~14 • receptors: G-protein coupled 7 transmembrane

  25. GRK b-arrestin recycling degradation a a b b PI-3K MAPK PLC SDF SDF g g p p target genes Adhesion, polarization, chemotaxis CCL12 (SDF) signaling Gai

  26. Cross-talk between Cytokine Signaling Pathways chemokine receptor interferon receptor IL, TLR, TNFa receptors TAK1 NFkB STATs TGFb receptor PI-3K

  27. Cytokines and Immunoregulation Mediators of Innate Immunity Mediators of adaptive immunity Stimulators of hematpoiesis

  28. Cytokines and Immunoregulation • Mediators of Innate Immunity • TNFa • IL-1 • IL-10 • IL-12 • IFNa, IFNb • IFNg • Chemokines Mediators of adaptive immunity • Stimulators of hematpoiesis

  29. Tumor Necrosis Factor a (TNFa) • Produced by activated macrophages and T cells • Most important mediator of acute inflammation in response to microbes, such as LPS • Induces production of myeloid CSFs, IFN-g, IL-6, IL-8 and other chemokines • Mediate recruitment of neutrophils and microphages to site of inflammation by stimulating cells to produce adhesion molecules (e.g. ICAM-1) • Stimulates endothelial cells and macrophages to produce chemokines • A potent pyrogen causing fever by direct action or via IL-1 • Promotes production of acute phase proteins, such as CRP • Roles in rheumatoid arthritis, psoriasis, tuberculosis, …

  30. prothrombotic macrophage activation lymphocyte development hematopoiesis

  31. Interleukin 1 (IL-1) • Produced by activated macrophages, stimulated lymphocytes, keratinocytes, fibroblasts • Activates the NFkB signaling pathway (similar effects to TNF) • Helps activate T cells • Can be induced by inflammation, injury, and infection

  32. Interleukin 10 (IL-10) • Produced by macrophages, B cells, Th2 cells • Originally identified as cytokine synthesis inhibitory factor • Suppresses inflammatory responses • Inhibits production of IFN-g, IL-2, IL-3, TNFa, GM-CSF • Stimulate thymocytes, mast cells, B cells • Limits Th1 response, promotes Th2 cell development, shifts response to Th2 type (phagocytosisAb production) • Inhibits expression of class II MHC and co-stimulatory molecules on macrophages

  33. Interleukin 12 (IL-12) • Produced by macrophages, dendritic cells, Tc cells, NK cells • Belongs to the IL-6 cytokine family • Has immunoregulatory effect on NK cells and T cells • Stimulates production of IFN-g • Promotes Th cells  Th1 • Enhances differentiation of Cytotoxic T Lymphocytes (with IL-2) • Enhances cytolytic functions of T cells and NK cells

  34. Type I Interferon (IFN-a, IFN-b) • Produced by macrophages and virus-infected cells • Inhibits viral replication in cells via PKR and RNaseL • Increases expression of MHC I and Tc mobilization • Stimulates production of IFN-g by activated T cells • Activate NK cells

  35. Type II Interferon (IFN-g) • Produced primarily by Th1 • Induce ICAM production in endothelial cells • Activate NK cells • Increase MHC I and MHC II expression to help Th cell and APC interaction • Promotes B cell differentiation to plasma cell • Promotes cytotoxic T cell differentiation

  36. Chemokines • Produced by many leukocytes and other types of cells • Large family of molecules (over 50) • Have significant structural homology and overlapping functions • Chemotactic for leukocytes, such as PMN, T and B cells • Recruit leukocytes to sites of infection and inflammation • Involved in lymphocytes trafficking, wound healing, metastasis, angiogenesis, lymphoid organ development….

  37. Cytokine in Immunregulation • Mediators of Innate Immunity • Mediators of adaptive immunity • IL-2 • IL-4 • IL-5 • TGFb • IL-10 • IL-12 • IFN-g Stimulators of hemotopoesis

  38. Interleukin 2 (IL-2) • Produced by lectin- or antigen-activated Th cells • Powerfully immunoregulatory lymphokine • Main growth factor for both T and B lymphocytes • Activates NK cells and monocytes CTLA-4: Cytotoxic T-Lymphocyte Antigen 4, inhibits T cell function.

  39. Interleukin 4 (IL-4) • Produced by macrophages, Th2 cells, activated B cells • Has complex biological actions via cytokine production • Enhances antigen-presenting activity of B to T cells • Stimulates development of Th2 cells from naïve Th cell • Stimulates Ig class switch from IgG1 to IgE (allergy)

  40. Interleukin 5 (IL-5) • Produced by Th2 cells • Originally identified as a B cell differentiation factor • Aids in the growth and differentiation of eosinophils and late-developing B cells to plasma cells

  41. Transforming growth factor b (TGFb) • Produced by T cells, macrophages, other cell types • 30 members • Have effect on many cell types • Have pro- and anti-inflammatory effect • Inhibits proliferation of T cells and activation of B cells • Acts on PMNs and endothelial cells to block the effects of pro-inflammatory cytokines

  42. Cytokine and Immunoregulation • Mediators of Innate Immunity • Mediators of adaptive immunity Stimulators of hematopoiesis(Colony Stimulating Factors) • GM-CSF: promotes differentiation of bone marrow progenitors • M-CSF: promotes growth and differentiation of monocytes and macrophages • G-CSF: promotes production of PMNs

  43. emdbiosciences.com

  44. Regulation of Immune Responses regulatory mechanisms: recognition phase

  45. Regulation of Immune Responses regulatory mechanisms: antibody antibody competes with B cells for antigen antigen/antibody complexes binding to Fc receptors sends an inhibitory signal to B cells

  46. Regulation of Immune Responses regulatory mechanisms: Tregs • Regulatory T cells (Tregs) do not inhibit initial T cell activation and proliferation • They are not Th1 or Th2 cells • They can suppress both Th1 and Th2 responses • They inhibit a sustained response and prevent chronic and potentially damaging responses

  47. Regulation of Immune Responses regulatory mechanisms: Tregs Naturally occurring Tregs CD4+CD25+Foxp3+ cells derived from thymus IL-2, cell contact dependent inhibition Foxp3 is required for Treg development CD25 (part of IL-2R) CD4 Foxp3

  48. Regulation of Immune Responses regulatory mechanisms: Tregs Induced Tregs CD4+CD25+Foxp3+ cells induced by antigen antige+IL-10 CD4 CD4 CD25 (part of IL-2R) TGFb Foxp3 Treg cells T cells

  49. Cytokines and Oral Diseases bacterial colonization bacterial invasion host responses chemokines: bone resorption, osteoclast survival IL-1: up-regulated, stimulates bone loss IL-6: proinflammatory to bone resorption TNFa: induces cytokine production, stimulate inflammation and bone loss RNAKL: inducer of osteoclast formation and activity, bone loss osteoclast formation/bone loss periodontal disease (PD)

  50. Cytokines and Clinical Applications Colony stimulating factors (CSFs) hematological disorders associated with cancer therapy Erythropoietin (EPO) anemia associated with kidney disease IFN-b multiple sclerosis IFN-g chronic granulomatous disease (GCD) IL-2 kidney cancer, melanoma IL-11 thrombocytopenia following high dose chemotherapy TNFa mAb Infliximab for rheumatoid arthritis and Crohn’s disease

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