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Cytokines and signaling pathways in healthy and disease

DENT516 Ge Jin, Ph.D. Email: ge.jin@case.edu Phone: 3683791 Office: DO3570, School of Dental Medicine. Cytokines and signaling pathways in healthy and disease. March 26, 2012. Learning Objectives: 1. What are cytokines?

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Cytokines and signaling pathways in healthy and disease

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  1. DENT516 Ge Jin, Ph.D. Email: ge.jin@case.edu Phone: 3683791 Office: DO3570, School of Dental Medicine Cytokines and signaling pathways in healthy and disease March 26, 2012

  2. Learning Objectives: 1. What are cytokines? 2. understand that NFkB and STAT proteins are transcription factors that modulate immune responses 3. understand that cytokines play important roles in PD

  3. Immune cells and the mediators they produce

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

  5. 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: TumorNecrosisFactor a (TNFa), ColonyStimulationFactor (CSF), TransformingGrowthFactorb (TGFb)….

  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. 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

  9. 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

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

  11. 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)

  12. -- 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)

  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 chemokine receptor family: CCR1-5, CXCR1-4 G-Protein-Coupled Receptor (GPCR)

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

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

  17. 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

  18. 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 TNFa 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

  19. 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 cytoplasm.

  20. cdc25a, cyclin D1~3, c-myc, cyclin E, MMP9 p21, caspase 3, 1, 8… SJ Baker et al, Oncogene (2007) 26, 6724–6737.

  21. Chemokine Signaling • 2 major families: the CCL (C-C motif ligand) family and CXCL (C-x-C motif ligand) family • CCL1~27, CXCL1~14 • receptors: G-protein coupled 7 transmembrane receptor (GPCR)

  22. 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

  23. pathogens/infection bacteria, virus inflammation chemokine production, recruitment of phagocytes…. increased blood supply, capillary permeability, leukocyte migration killing of pathogens neutralizing toxins, limiting pathogen spread tissue repair phagocytosis of debris, pathogens, dead cells; cells growth resolution elimination of a pathogen, disappearance of leukocytes, full regeneration of tissue function

  24. Failure of acute inflammation resolution leads to chronic inflammation and autoimmune disorders Examples: periodontal diseases (PD) chronic inflammation after dental treatment

  25. Cytokines and Periodontal Diseases (PD) • the most common diseases in the world and the leading cause of tooth loss, a chronic infection that slowly attacks and destroys the gums and bone that support the teeth. • caused by bacterial (~200 species) infection • followed by a persistent immune response • resulted in tissue damage

  26. bacteria A. actinomycetemcomitans, P. gingivalis, B. forsythus, T. denticola, T. socranskii, P. intermedia cell wall components (lipopolysaccharides, LPS) exotoxins hydrolytic enzymes inhibit antimicrobial peptides (lysozymes) activity toxic to phagocytes (macrophages) tissue damage/bone resorption stimulate cytokine production of immune cells/chronic inflammation

  27. phagocytosis H2O2, NO AMP Bacteria LPS, exotoxin, etc. binding to Toll-like receptors (TLRs) activation of the NFkB signaling pathway in immune cells and epithelial cells TNFa, IL-1, IL-6, IL-8, IFNa/b, chemokines… neutrophils macrophages dendritic cells (DCs) T cells B cells perodontitis (autoimmune disorder)

  28. 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 • produced by the LPS-membrane bound Toll-like receptors (TLRs) • mediates recruitment of neutrophils and microphages to site of inflammation • 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, …

  29. TNFa and PD • high in diseased periodontal tissues • influences leukocyte migration • corrected with RANKL and matrix metalloproteinase (MM) production • stimulates IL-1, IL-8, IL-6 proinflammatory cytokine production • central role in inflammatory reaction, alveolar bone resorption, and the loss of connective tissue attachment

  30. 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

  31. Summary (PD and cytokines) TNFa and IL-1 play critical roles in amplifying the inflammatory response, leading to production of lytic enzymes and proinflammatory cytokines in PDs. TNFa and IL-1 antagonists block the progression of the inflammatory cell infiltrate and prevent the periodontal lesions

  32. 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)

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