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Inflammatory Mediators Corrigan


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Inflammatory Mediators Corrigan

  1. 1. Inflammatory mediators Dr Chris Corrigan Reader/Consultant GKT School of Medicine
  2. 2. Mediators of Inflammation <ul><li>Cytokines </li></ul><ul><li>Chemokines </li></ul><ul><li>Lipid mediators (leukotrienes, prostaglandins) </li></ul><ul><li>Neuropeptides </li></ul><ul><li>Endothelin and NO </li></ul>
  3. 3. Cytokines
  4. 4. Cytokines (1) <ul><li>Soluble (glyco)proteins produced by leucocytes and other cell types </li></ul><ul><li>Chemical communicators between cells, but usually not end effector molecules </li></ul><ul><li>Bind to specific receptors on the surface of target cells </li></ul><ul><li>Most are growth/differentiation factors for haematopoietic cells; some have systemic effects </li></ul>
  5. 5. Cytokines (2) <ul><li>Pleiotropicitiy and redundancy of functional effects </li></ul><ul><li>Tend to mediate localised effects (very short half-life in circulation), although some act systemically </li></ul><ul><li>Receptors typically comprise two or more polypeptide chains which can be grouped into families </li></ul>
  6. 6. Cytokines (3) <ul><li>Act not singly but in patterns </li></ul><ul><li>Typically , any one cytokine will affect the expression of other cytokines and/or their receptors </li></ul><ul><li>Problem of implicating particular cytokines in disease processes: </li></ul><ul><li>Correlation with disease severity </li></ul><ul><li>Use of agonists and antagonists </li></ul>
  7. 7. Regulation of cytokine expression <ul><li>Constitutive (steady state haematopoiesis, e.g. M-CSF, G-CSF, SCF, IL-6) </li></ul><ul><li>Stored pre-synthesised: </li></ul><ul><li>In granules (e.g. GM-CSF, TGF-  </li></ul><ul><li>On membranes (e.g. TNF-  ) </li></ul><ul><li>Complexed to extracellular matrix (e.g. TGF-  ) </li></ul><ul><li>Most are not constitutively expressed but synthesised rapidly in response to stimulation and/or other cytokines </li></ul>
  8. 8. Other cytokine control mechanisms <ul><li>Processing (cleavage, precursors) </li></ul><ul><li>Sequestration </li></ul><ul><li>Soluble binding proteins (including soluble receptors) </li></ul><ul><li>Naturally occurring antagonists (IL-1RA) </li></ul><ul><li>Modulation of receptors </li></ul>
  9. 9. Cytokine receptor superfamilies <ul><li>Ig constant region-like domains (C1, C2) </li></ul><ul><li>Complement control protein domains </li></ul><ul><li>Fibronectin type III domains (FNIII) </li></ul><ul><li>Cytokine receptor domains (CK) </li></ul>
  10. 10. Cytokine receptor superfamilies Superfamily Receptors for Common structure Cytokine receptor IL-2 (  ), IL-4, Single spanning membrane IL-3/5 (  ), IL-6, glycoporteins with CK, IL-9, IL-12, etc. FNIII and C2 Ig domains Interferon receptor IFN-  , IL-10 SSMG, FNIII domains Immunoglobulin IL-1, IL-6, FGF, Domains containing the M-CSF, SCF “Ig fold” Protein tyrosine EGF, PDGF, M-CSF Intracellular PTK domains kinase receptor SCF, FGF NGF receptor NGF, TNF-I/II 3-4 cysteine-rich repeats in extracellular molecule G-protein coupled C5a, PAF, 7 transmembrane domains 7 transmembrane IL-8 and chemokines with 3 extra- and 4 intra- spanning receptor cellular loops Complement protein IL-2(  ), complement Multiple repeats short domains
  11. 11. “Pro-inflammatory” cytokines: IL-1, TNF-  , IL-6 <ul><li>Broad range of pro-inflammatory properties locally and systemically </li></ul><ul><li>Cachexia, fever, neutrophilia, acute-phase response </li></ul>
  12. 12. Interleukin-1 (1) <ul><li>Two forms, IL-1  with only 20% homology but very similar activity </li></ul><ul><li>Pro-peptides cleaved extracellularly by neutral proteases </li></ul><ul><li>Natural inhibitor IL-1RA </li></ul><ul><li>Monocyte/macrophages, keratinocytes, epithelium, T cells, LGL, B cells, endothelium, Langerhans, dendritic, fibroblasts, neutrophils, eosinophils, smooth muscle, etc. </li></ul>
  13. 13. Interleukin-1 (2) <ul><li>Stimuli: toxins, haemaggluitinins, C5a, TNF-  , antigen-specific T cell contact </li></ul><ul><li>Two receptors IL-RI/II (Ig superfamily) on leucocytes, dendritic, fibroblast, neural, endothelium, etc. </li></ul>
  14. 14. Interleukin-1 (3) <ul><li>Effects: </li></ul><ul><li>Haematopoiesis </li></ul><ul><li>Cytostatic to tumour cells; enhances cell-mediated tumour killing </li></ul><ul><li>Other cytokines: IL-6, IL-8, TNF-  , etc. </li></ul><ul><li>Fever, acute phase response </li></ul><ul><li>T cell proliferation following antigen-specific activation </li></ul><ul><li>Development of pre-B cells </li></ul>
  15. 15. TNF-  and IL-6 TNF-  IL-6 Source Many Many Structure Pro-peptide; trimerises Single peptide Tumour suppression +++ + Acute phase response +++ ++ Receptor TNFRI/II (CD120a/b) Heterodimer  -chain CD126  -chain CD130 Receptor distribution Widspread Widespread Endothelium T cells, B cells, T cells, APC plasma cells
  16. 16. IL-2 and IL-15 IL-2 IL-15 Source Activated T cells Multiple (T cell, (B cells) placenta, muscle, epithelium, monocytes) Actions T cell autocrine/paracrine growth factor B cell differentiation and Ig secretion Monocytes: IL-1 secretion, cytotoxicity, phagocytosis NK cells, LAK cells Receptor  subunits  chains of IL-2R Receptor subunits  other names CD25, Tac, p55 CD122, p75 Kd (nM) 10 1000 none signal transduction no yes yes
  17. 17. IL-4 and IL-13 IL-4 IL-13 Source “Th2-type” CD4 T cells “Th1/0/2”-type T cells Some CD8 T cells Some CD8 T cells Thymocytes, eosinophils, mast cells, basophils Actions B cells: class II MHC, CD40, CD23, Ig synthesis IgE class switching (not in the mouse!) Growth and proliferation No effect on T cells of T cells “ Th2-type” T cells Monocytes: complex effects: MHC class II, antigen presentation, cytokine release
  18. 18. IL-10 <ul><li>Homologous to BCRF1 (EBV genome) </li></ul><ul><li>T cells, B cells, monocyte/macrophages </li></ul><ul><li>Inhibits cytokine synthesis by “Th1-like” T cells and NK cells, and antigen presentation and cytokine (TNF-  , IL-6, IL-8) production by macrophages </li></ul><ul><li>Enhances activation and maturation of B cells (Ig synthesis), thymocytes, mast cells </li></ul>
  19. 19. IL-3, IL-5 and GM-CSF <ul><li>Common signal-transducing  -chain in heterodimeric receptors </li></ul><ul><li>Clustered on chromosome 5 (with IL-4, M-CSF) </li></ul><ul><li>Activated T cells, mast cells, eosinophils </li></ul><ul><li>IL-5 is uniquely eosinophil-specific </li></ul><ul><li>IL-3: pluripotential stem cells, granulocyte/macrophage/erythroid/platelet precursors </li></ul><ul><li>GM-CSF: mature granulocytes and monocytes </li></ul>
  20. 20. IL-12 <ul><li>Heterodimer 35/40 kDa </li></ul><ul><li>Induces IFN-  synthesis, NK and LAK activity independently of IL-2 (CMI) </li></ul><ul><li>Induces “Th1-type”, but inhibits “Th2-type” T cell responses </li></ul><ul><li>Inhibits IgE synthesis by B cells </li></ul>
  21. 21. Interferon-  <ul><li>T cells and NK cells </li></ul><ul><li>Antiparallel homodimer </li></ul><ul><li>Receptor: single transmembrane protein with accessory protein. Expressed on T/B cells, APC, granulocytes, epithelial cells, endothelial cells, tumour cells </li></ul><ul><li>Inhibits viral replication </li></ul><ul><li>Activates macrophages: tumoricidal, microbicidal, IL-1, IL-6, TNF-  </li></ul><ul><li>Class II MHC expression </li></ul><ul><li>Prototype “Th1-type” cytokine </li></ul>
  22. 22. Th1 Th2 IL-2 IFN-  IL-4 IL-5 TNF-  IL-6 IL-3 IL-10 GM-CSF IL-13 IL-9? Cytolysis Help for IgE synthesis Help for IgG/A/M synthesis Th0 TNF-  Cytokines
  23. 23. IFN-  IL-4 IL-13 Th1 Th2 Th0 IL-12 IFN-  IFN-  NK IL-4 IL-13 Mast IL-4 - - M  + - + +
  24. 24. Interleukin-18 <ul><li>Actions </li></ul><ul><li>Growth of T cells and NK cells with production of IFN-  , TNF-  </li></ul><ul><li>Synergises with IL-12 to induce IL-18R on T cells and activated B cells causing IFN-  release and inhibition of IgE synthesis </li></ul><ul><li>Sources </li></ul><ul><li>Monocyte/macrophages, intestinal epithelial cells, osteoblasts </li></ul>
  25. 25. Interleukin-18 (2) pro-IL-18 18 kDa caspase 1 (IL-1  CE) <ul><ul><ul><li>Structure: similar to IL-1  </li></ul></ul></ul><ul><li>Receptor: IL-1R related protein </li></ul>
  26. 26. Cytokines and Th1/2 T cell development Pro-Th1 cytokines Pro-Th2 cytokines IFN-  IL-4 IL-12 IL-18 IFN- 
  27. 27. Interleukin-16 (1) <ul><li>Actions </li></ul><ul><li>CD4 ligand, causing activation and chemotaxis of CD4 bearing cells (CD4 T cells, monocytes, eosinophils) (“lymphocyte chemotactic factor”) </li></ul><ul><li>Resistance to HIV-1 replication (2,4,9 kb transcripts), but not cellular penetration </li></ul><ul><li>Sources </li></ul><ul><li>Epithelium, T cells, mast cells, macrophages, eosinophils </li></ul>
  28. 28. Interleukin-16 (2) 20 kDa 30 kDa pro-IL-16 caspase 3 121 HIV-1 tetramers CD4 ligand
  29. 29. IL-16 and allergic inflammation mast cell IL-5, GM-CSF Rantes, MIP-1  eotaxin IL-16 histamine IL-5 LTB 4 + eosinophil CD4 T cell CD4 CD4
  30. 30. Interleukin-17 <ul><li>T cell regulation of haematopoiesis </li></ul><ul><li>Enables fibroblasts to sustain CD34+ precursor cells and direct maturation towards neutrophils ? Via IL-6, IL-8, G-CSF </li></ul>
  31. 31. IL-10 family:  -helices <ul><li>IL-19: monocytes, B cells </li></ul><ul><li>IL-20: monocytes (keratinocytes) </li></ul><ul><li>IL-22/TIF: NK, CD4+ Th1 cells </li></ul><ul><li>IL-24/mda-7: T cells, melanocytes, monocytes, NK cells, B cells </li></ul><ul><li>IL-26/AK155: CD4 T memory cells, NK cells </li></ul><ul><li>Receptors: class II (CRF2):  and  chains </li></ul>
  32. 32. Interleukin-21 <ul><li>4  -helix cytokine most closely related to IL-15 </li></ul><ul><li>Secreted by CD4 T cells in response to antigen stimulation </li></ul><ul><li>Differentiation of NK cells (CD16, IFN-  ) </li></ul><ul><li>Blocks further recruitment of activated NK cells </li></ul>
  33. 33. Interleukin-23 <ul><li>2 subunits p19 and p40 </li></ul><ul><li>p19 4  -helix cytokine related to p35 subunit of IL-12 </li></ul><ul><li>p40 is subunit of IL-12 </li></ul><ul><li>Engages IL-12R  2 </li></ul><ul><li>Memory cell proliferation and IFN-  production </li></ul><ul><li>Dendritic cells </li></ul>
  34. 34. Chemokines
  35. 35. Chemokines <ul><li>Small MW (8-10 kDa) peptides: mediators of acute inflammatory responses </li></ul><ul><li>Chemotactic cytokines </li></ul><ul><li>Chemoattraction, activation, diapedesis of granulocytes (also T cells/monocytes) </li></ul><ul><li>Angiogenic </li></ul><ul><li>Bind to heparin and stromal proteoglycans </li></ul><ul><li>IgE-independent basophil degranulation </li></ul>
  36. 36. Chemokine families CXCL 1-15 Two cysteines separated by one amino acid Chromosome 4q12-q21, 10 24-84% homology N-terminal Glu-Leu-Arg (ELR) (neutrophil active) or non-ELR (not neutrophil active) CCL 1-28 Two adjacent cysteines Chromosome 17 25-71% homology CL 1/2 One cysteine Chromosome 1 CX3CL 1
  37. 37. Chemokine receptors <ul><li>Seven transmembrane spanning G-protein coupled receptor superfamily </li></ul><ul><li>6 CXCR chemokine, 10 CCR chemokine receptors cloned, more to come </li></ul><ul><li>CXCR 4, CCR 5, CCR 3 mediate entry of HIV into T cells/monocytes </li></ul><ul><li>Most chemokines bind to several receptors </li></ul><ul><li>CCR 3: confined to eosinophils and Th2-type T cells: binds to eotaxin, RANTES, MCP-2/3/4 </li></ul>
  38. 38. Chemokine receptors <ul><li>G-protein coupled, 7 transmembrane spanning </li></ul><ul><li>Chemokine selectivity and range of expression on leukocytes overlap extensively </li></ul><ul><li>Some constitutive, some inducible, some susceptible to down-regulation </li></ul>
  39. 39. CXCL chemokines <ul><li>Neutrophil chemotaxis (IL-8 most potent) </li></ul><ul><li>T cell chemotaxis (e.g. IL-8 CD8+ T cells) </li></ul><ul><li>Neutrophil activation </li></ul><ul><li>Suppress (IL-8, GRO-  , PF4) or stimulate (SDF-1) myeloid colony formation </li></ul><ul><li>Stimulate (ELR subgroup) or suppress (non-ELR subgroup) angiogenesis </li></ul><ul><li>Fibroblast collagen synthesis (CTAP III) </li></ul><ul><li>Post-translational modification, e.g. PBP and NAP-2 </li></ul>
  40. 40. Some CXCL chemokines CXCR 3 IP-10 CXCL 10 CXCR 3 MIG CXCL 9 CXCR 1/2 IL-8 CXCL 8 CXCR 2 NAP-2 CXCL 7 CXCR 2 ENA-78 CXCL 5 PF 4 CXCL 4 CXCR 2 GRO  CXCL 1-3
  41. 41. CCL chemokines <ul><li>Monocyte/lymphocyte chemotaxis/activation: MIP-1  (CD4+), RANTES (CD4/CD45RO+) </li></ul><ul><li>Eosinophil chemotaxis/activation: eotaxin, eotaxin 2 (eosinophils only), RANTES, MCP-3, MCP-4, (MCP-2, MIP-1  ) </li></ul><ul><li>Histamine releasing activity: MCP-1, MCP-3, MIP-1  , RANTES, MCP-2 </li></ul><ul><li>HIV anti-viral effects: RANTES, MIP-1  , MIP-1  </li></ul><ul><li>Post-translational modification, e.g. CD26 and RANTES, eotaxin </li></ul>
  42. 42. Some CCL chemokines CCR 3 Eotaxin 2/3 CCL 24/26 CCR 4 TARC CCL 17 CCR 2/3 MCP-4 CCL 13 CCR 3/5 Eotaxin CCL 11 CCR 1/2/3 MCP-3 CCL 7 CCR 1/3/5 RANTES CCL 5 CCR 1/5 MIP-1  CCL 3/4 CCR 2 MCP-1 CCL 2 CCR 8 I-309 CCL 1
  43. 43. Chemokine receptor expression by T cells <ul><li>Th1 </li></ul><ul><li>CXCR 3 </li></ul><ul><li>Th2 </li></ul><ul><li>CCR 3 </li></ul><ul><li>CCR 4 </li></ul><ul><li>CCR 8 </li></ul>
  44. 44. Cooperation between eotaxin and IL-5 in eosinophil accumulation eotaxin IL-5 eosinophils & precursors eosinophils Eotaxin mediated but IL-5 dependent Bone marrow Tissues
  45. 45. Eotaxin, eosinophils and “Th2-type” T cells Th2 T cell Eosinophil CCR3 CCR3 eotaxin eotaxin IL-5 GM-CSF
  46. 46. Sources of eotaxin <ul><li>Epithelial cells </li></ul><ul><li>Endothelial cells </li></ul><ul><li>T cells </li></ul><ul><li>Eosinophils </li></ul><ul><li>Fibroblasts </li></ul>
  47. 47. Lipid mediators (leukotrienes, prostaglandins)
  48. 48. Leukotrienes and prostanoids <ul><li>Ubiquitous oxygenated fatty acids </li></ul><ul><li>Physiological functions: temperature regulation, coagulation, parturition, blood pressure </li></ul><ul><li>Newly formed mediators </li></ul>
  49. 49. 5(S)-HETE Prostaglandins Thromboxanes LTB 4 Nuclear membrane phospholipids 5(S)-HPETE LTA 4 LTC 4 LTD 4 Arachidonic acid LTE 4 Phospholipase A 2 5-lipoxygenase 5-lipoxygenase LTA 4 hydrolase  -glutamyl transpeptidase LTC 4 synthase Dipeptidases Cyclooxygenase
  50. 50. Cellular sources of leukotrienes Predominantly LTB 4 Predominantly LTC 4 /D 4 /E 4 Monocytes Monocytes Eosinophils Macrophages Macrophages Mast cells Neutrophils Basophils (B cells) Reflects restricted expression of 5-lipoxygenase LTC 4 synthase and LTA 4 hydrolase are widely expressed
  51. 51. Biological activities of leukotrienes LTB 4 LTC 4 /D 4 /E 4 Increase leucocyte adhesion to endothelium Increase microvascular permeability Neutrophil (eosinophil) chemotaxis Vasoconstriction Neutrophil lysosomal release Smooth muscle contraction and superoxide generation Increase mucus secretion Bronchoconstriction (via TXA 2 ) CD8 T cell cytotoxicity IgG production Augment IL-2, IFN-  production
  52. 52. Leukotriene degradation <ul><li>LTB 4 </li></ul><ul><li>20-  hydroxylation </li></ul><ul><li>Further oxidation to aldehyde and acid </li></ul><ul><li>LTC 4 </li></ul><ul><li>Conversion to LTD 4 /E 4 </li></ul><ul><li>Extracellular metabolism (H 2 O 2 ) (sulphoxides) </li></ul><ul><li> -oxidation </li></ul>
  53. 53. Leukotriene receptors <ul><li>LTB 4 </li></ul><ul><li>LTB 4 (B-LT) receptor </li></ul><ul><li>LTC 4 /D 4 /E 4 </li></ul><ul><li>CysLT1: inflammatory cells, smooth muscle </li></ul><ul><li>CysLT2: inflammatory cells, vascular smooth muscle </li></ul><ul><li>Others? </li></ul>
  54. 54. Leukotrienes in disease <ul><li>Bronchial asthma and allergic rhinitis </li></ul><ul><li>Fibrosing lung disease </li></ul><ul><li>Infant/adult respiratory distress syndrome </li></ul><ul><li>Rheumatoid arthritis </li></ul><ul><li>Psoriasis </li></ul><ul><li>Inflammatory bowel disease </li></ul><ul><li>Myocardial infarction </li></ul>
  55. 55. Leukotriene inhibitors <ul><li>LTD 4 receptor antagonists </li></ul><ul><li>Zafirlukast </li></ul><ul><li>Pranlukast </li></ul><ul><li>Montelukast </li></ul><ul><li>5-lipoxygenase inhibitors </li></ul><ul><li>Zileuton </li></ul>
  56. 56. Prostanoids Arachidonic acid 15-keto-PGE 2 PGG 2 PGH 2 PGE 2 PGH synthase (cyclooxygenase) 15-keto-PGF 2  PGF 2  6-keto-PGF 1  PGI 2 (prostacyclin) TXB 2 TXA 2 (thromboxane) 9  ,11  PGF 2  PGD 2
  57. 57. Biosynthesis and cellular sources PGH synthase 2 (COX) isoforms: COX-1 (ubiquitous, constitutive) COX-2 (inducible in inflammation) Major products characteristic of different cells: Mast cells PGD 2 Platelets TXA 2 Endothelium PGI 2 Smooth muscle PGI 2 Epithelium PGE 2 Macrophages PGF 2  , PGE 2 , TXA 2
  58. 58. Prostanoid receptors PGD 2 DP PGE 2 EP-1(smooth muscle contraction)/2(relaxation)/3/4 PGF 2  FP PGI 2 IP TXA 2 TP-1/2 (more?) G-protein linked 7 transmembrane domain proteins Considerable cross-reactivity between receptors
  59. 59. Prostanoids: pro-inflammatory actions <ul><li>Pain </li></ul><ul><li>Swelling </li></ul><ul><li>Vascular engorgement </li></ul><ul><li>Smooth muscle contraction/relaxation </li></ul>
  60. 60. Neuropeptides
  61. 61. Tachykinins <ul><li>Substance P (SP), neurokinin A/B </li></ul><ul><li>Neuropeptide K (NPK), NP-  </li></ul><ul><li>Found in neurons in the CNS only (NKB), or in the CNS and peripheral nerves (SP, NKA) </li></ul><ul><li>Somatic sensory (C-fibre) nerves </li></ul><ul><li>Sensitive to capsaicin </li></ul>
  62. 62. Tachykinins: receptors and metabolism Receptors NK 1 NK 2 NK 3 Affinity SP>NKA=NKB NKA>NKB>>SP NKB>NKA>>SP Distribution Wide Wide Brain & spinal cord Metabolism Angiotensin converting enzyme (ACE): endothelium Neutral endopeptidase (NEP): epithelium
  63. 63. Tachykinins: inflammatory efects <ul><li>Non-adrenergic, non-cholinergic (NANC) effects of peripheral nerve stimulation </li></ul><ul><li>Direct or via axon reflexes: “neurogenic inflammation” </li></ul><ul><li>Smooth muscle contraction, plasma leakage, mucus secretion, vasodilatation </li></ul><ul><li>Mast cell degranulation (SP) </li></ul><ul><li>Priming and adherence of granulocytes </li></ul>
  64. 64. Calcitonin gene-related peptide (CGRP) <ul><li> -CGRP (separate gene) </li></ul><ul><li> -CGRP (alternative splicing of calcitonin gene) </li></ul><ul><li>Widely distributed in peripheral neurones </li></ul><ul><li>Metabolised by mast cell tryptase and chymase (also NEP) </li></ul><ul><li>High-affinity binding sites in vascular smooth muscle </li></ul>
  65. 65. CGRP: pro-inflammatory effects <ul><li>Relaxation of smooth muscle, particularly large and small blood vessels, mediated via NO release </li></ul><ul><li>Enhances, but does not cause vascular leakage </li></ul><ul><li>Increases neutrophil adherence, inhibits T cell proliferation </li></ul>
  66. 66. Other neuropeptides <ul><li>Vasoactive intestinal peptide (VIP) </li></ul><ul><li>VIP-related peptides (PHM, PHV, helodermin, helospectins) </li></ul><ul><li>Neuropeptide tyrosine </li></ul><ul><li>Opioids </li></ul><ul><li>Gastrin-releasing peptide </li></ul><ul><li>Galanin </li></ul>
  67. 67. Other possible effects of neuropeptides <ul><li>Pain and hyperalgesia </li></ul><ul><li>Smooth muscle contraction </li></ul><ul><li>Vascular leakage </li></ul><ul><li>Arthritis: pain, fibroblast and synoviocyte proliferation </li></ul>
  68. 68. Endothelin (ET) and nitrous oxide (NO) ET (vasoconstriction) NO (vasodilatation) Vascular endothelium and endocardium Epithelial cells Peripheral NANC nerves CNS Placenta Inflammatory leucocytes
  69. 69. Endothelin (ET) and nitrous oxide (NO): synthesis ET NO pro-ET ET 1-3 L-arginine L-citrulline + NO N G -hydroxy-L-arginine big ET NADPH NADP O 2 H 2 O NADPH NADP O 2 H 2 O
  70. 70. NO synthase: isoforms Isoform Expression Distribution nNOS constitutive CNS, peripheral NANC nerves, epithelium eNOS constitutive endothelium, placenta (membrane anchored) iNOS inducible many cells IL-1, TNF-  , IFN-  , LPS stimulatory TGF-  , corticosteroids inhibitory
  71. 71. ET and NO: signalling ET 7 transmembrane domain receptor coupled to G-protein Activates PLC and PKC, AP-1, gene expression NO Acts by local diffusion Binds to haem moiety of guanylyl cyclase, elevating cGMP Non-specific cytotoxic/cytostatic effects: forms peroxynitrate which binds to Fe 2+
  72. 72. Mediators of Inflammation <ul><li>Cytokines </li></ul><ul><li>Chemokines </li></ul><ul><li>Lipid mediators (leukotrienes, prostaglandins) </li></ul><ul><li>Neuropeptides </li></ul><ul><li>Endothelin and NO </li></ul>