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Understanding Inflammation Cytokines and Their Roles

Learn about the role of cytokines in inflammation, including TNF, IL-1, and IL-6. Explore the effects of chemokines, ROS, NO, lysosomal enzymes, and neuropeptides in inflammatory responses.

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Understanding Inflammation Cytokines and Their Roles

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  1. Inflammation Dr. Ahmad Hameed MBBS,DCP, M.Phil

  2. Cytokines • Polypetide products of many cell types that function as mediators of inflammation and immunity • Some stimulate bone marrow precursors to produce more WBCs • Some mediate communication between WBCs(Interleukins) • Major cytokines in acute inflammation(TNF, IL-1) and chronic inflammation (IFN-γ ,IL-12)

  3. TNF & IL-1 • Produced by macrophages, mast cells, endothelial cells • Stimulated by microbial products, immune complexes, products of T-lymphocytes • Endothelial effects • Endothelial activation expression of adhesion molecules • WBC binding & recruitment • Procoagulant activity by TNF • Increase in IL-1,IL-6,IL-8,PDGF, eicosanoids • Fibroblast effects • Activates tissue fibroblasts • Increases proliferation, production of collagen &ECM

  4. Systemic Effects • Fever • Lethargy • Increased sleep • Decreased appetite • Hepatic synthesis of acute phase proteins • Metabolic wasting • Corticosteroids Synthesis • Neutrophil release in circulation • Fall in blood pressure

  5. The roles of cytokines in acute inflammation. The cytokines TNF, IL-1, and IL-6 are key mediators of leukocyte recruitment in local • inflammatory responses and also play important roles in the systemic reactions of inflammation.

  6. Chemokines • Family of small 8-10 kDa proteins • Helps in recruitment and activation of Leukocytes • Responsible for anatomic distribution of B & T lymphocytes in different areas of lymph nodes & spleen • Mediate their activities by binding to specific G-protein coupled receptors on target cells. • Receptors: CXCR4, CCR5

  7. Chemokines • CXC • One amino acid separating the cysteines • Act primarily on neutrophil • IL-8 • Produced by macrophages, endothelial cells, mast cells, fibroblasts • Produced in response to microbial products, IL-1 and TNF • CC • Adjacent cysteine residues • MCP-1, MIP-1α • RANTES • Eotaxin

  8. ROS • Produced by NADPH oxidase in neutrophils & macrophages • Activated by microbes, immune complexes, cytokines • With in lysosome destroy phagocytosed microbes and nectrotic cells • At low levels, increases cytokines & adhesion molecule expression ,destroy phagocytosed microbes & necrotic tissues • At high levels, cause tissue injury by endothelial damage, breakdown of ECM because of protease activation and an • Direct injury to other cell types ,inactivation of anti-proteases • Protective mechanisms( Catalase, Superoxide dismutase & Glutathione)

  9. NO • Short lived, soluble, free radical gas • Produced by neurons, macrophages & endothelial cells • nNOS, iNOS(IL-1, TNF, IFN-γ, bacterial endotoxins) also present hepatocytes, cardiac myocytes, resp epithelial cells, eNOS • Functions • Cytotoxic to microbes(Microbicidal) • Vasodialation • ↑ Increase vascular permeability • Inhibits platelet adhesion,aggregation & degranulation • Inhibits WBC adhesion & recruitment • ↓ Decrease cellular response

  10. Lysosomal Enzymes of WBCs • Capable of phagocytosis and tissue damage • Acid proteases • Active only within phagolysosomes • Neutral proteases • E.g. Elastase,Collagenase,Cathepsin • Active in ECM, degrade elastin, collagen & other matrix proteins • Convert C3 & C5 to C3a & C5a • Can convert HMWK to Bradykinin

  11. Destructive Effects of Lysosomal Enzymes • Proteases are checked by Anti-proteases e.gα1-antitrypsin is inhibitor of neutrophilelastase and α2 – macrogloblin • α1-antitrypsin deficiency in the lungs cause severe panacinar emphysema

  12. Neuropeptides ( e.g Substance P) • Initiates inflammation • Transmit pain signals • Regulate vessel tone & thus vascular permeability • Secreted by sensory nerves (lungs, GIT) and leukocytes. • Stimulation of secretion by endocrine cells • Regulate blood pressure

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