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Lecturer: Ge Jin, Ph.D., [email protected], 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. Body as Host: Immune Molecules Cytokines properties, categories, signaling, function Cytokines small, secreted, non-antibody proteins produced by cells involved in both innate & adaptive immunity mediate and regulate immunity, inflammation, and hematopoiesis 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 Factor b (TGFb)…. 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), colonystimulation factors (CSF) 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) Properties of Cytokines can be produced by many cell types and act on many cell types (pleiotropic) different cytokines can have similar actions (redundant) -- 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 Xlinked SCID (Severe Combined Immunodeficiency) 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 Cytokine Receptors (grouped by structures into families) Immunoglobulin superfamily: IL1R, TLRs… leucine-rich repeats immunoglobulin domain cell membrane Toll-IL-1 Receptor domain (TIR) IL-1 receptor Toll-like receptors (TLRs) Cytokine Receptors TNFR family: TNFa, FasL, CD40L… Cytokine Receptors class I receptor family: hematopoietin family CNTF LIF/OSM IL-6 GM-CSF IL-3 IL-5 b IL-2b g IL-9R IL-7 IL-9 IL-7R IL-15Ra IL-2Ra IL-5R IL-3R b g IL-15 g g IL-2b cell membrane GM-CSF: Granulocyte macrophage colony-stimulating factor IL: interleukin gp130: glycoprotein 130 (m.w. 130 kDa) CNTFR GM-CSFRa IL-2 b IL-11 gp130 gp130 gp130 gp130 cell membrane Cytokine Receptors class II receptor family: Interferon a, b, and g IFNARI IFNgRb IFNAR2b IFNAR2c cell membrane type I IFN receptor type I IFN: IFNa and IFNb, type II: IFNg IFNgRa type II IFN receptor Cytokine Receptors chemokine receptor family: CCR1-5, CXCR1-4 NH3 cell membrane binding of a ligand to the receptor Cytokine Receptors TGFb receptors TGFb receptors have intrinsic kinase activity when interacting with ligands. Cytokine Signaling cytokines binding membrane receptors signal transduction phosphorylation cascades activation transcription, Ca++… Cytokine Signaling NFkB signaling pathways JAK/STAT signaling pathways Chemokine signaling pathways Cross-talk between pathways NFkB Signaling Nuclear Factor k B (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 IL-1 p IRAK4 pellino1 pellino1 Tollip MyD88 p IRAK p p IRAK p IRAK4 TRAF6 TRAF6 complex I IL-1 receptor p u IRAK p TAB1 TRAF6 TAB2 TAK1 TAB3 p p IRAK p p u u complex II degradation p IkB NFkB p p IkB u u IkB u Ubc13/Uev1A u TRAF6 TAB2 TAK1 TAB3 p TAB1 p IKKb IKKa TAK1 complex III IkB u u nucleus p p NFkB p ubiquitination& degradation TF NFkB p p TF phosphorylation u ubiquitination p IL-6 IL-8 hBD-2 …. innate & adaptive immunity NFkB Signaling Alternative NFkB activation pathways of immunity CD40L, LT-B, BAFF CD4/TCR UV-light NIK PKC p38-CKII IkB degradation NFkB activation JAK/STAT Signaling Pathway JAK (Janus Kinases): a family of tyrosine kinases, JAK1-3, Tyk2 STAT (Signal Transducers and Activators of Transcription): 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 SJ Baker et al, Oncogene (2007) 26, 6724–6737. IFNa/b IFNg receptor target gene transcription cdc25a, cyclin D1~3, c-myc, cyclin E, MMP9 p21, caspase 3, 1, 8… DNA Receptor JAKs Receptor JAKs STATs nucleus STAT dimers Chemokine Signaling 2 major families: the CCL family and CXCL family CCL1~27, CXCL1~14 receptors: G-protein coupled 7 transmembrane CCL12 (SDF) signaling Gai b a g b PI-3K p p GRK a b-arrestin g MAPK PLC recycling degradation target genes Adhesion, polarization, chemotaxis Cross-talk between Cytokine Signaling Pathways chemokine receptor interferon receptor IL, TLR, TNFa receptors TAK1 STATs PI-3K NFkB TGFb receptor Cytokines and Immunoregulation Mediators of Innate Immunity Mediators of adaptive immunity Stimulators of hematpoiesis 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 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, … prothrombotic macrophage activation hematopoiesis lymphocyte development 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 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 (phagocytosisAb production) Inhibits expression of class II MHC and co-stimulatory molecules on macrophages 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 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 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 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…. 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 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. 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) 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 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 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 emdbiosciences.com Regulation of Immune Responses regulatory mechanisms: recognition phase 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 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 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 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 T cells Treg cells 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) 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 Cytokines properties, categories, signaling, function What are cytokine? Interleukines, chemokines, monokines, … cytokine receptors NFkB, JAK/STATA, chemokine signaling pathways role of cytokines in immunomodulation cytokines and oral diseases (PD)