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Chemokines

Chemokines. Dr. habil. Kőhidai, László Chemotaxis Research Group Dept. Genetics, Cell- & Immunobiology, Semmelweis University 2011. . Classification of chemokines . Characterization of IL-8 chemokine . Dimerization of chemokines .

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Chemokines

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  1. Chemokines Dr. habil. Kőhidai, László Chemotaxis Research Group Dept. Genetics, Cell- & Immunobiology, Semmelweis University 2011.

  2. Classification of chemokines

  3. Characterization of IL-8 chemokine

  4. Dimerization of chemokines The CXC chemokines have a six stranded beta sheet dimer and the CC chemokines have an end-on-end dimer.  It was first thought that dimers were necessary for function of chemokines but tests have proven that chemokines can function as monomers.  It is possible that dimerizartion is just more thermodynamically favored

  5. chemokine NH2- receptor HOOC- Receptor-ligand interaction GAG Signalling

  6. Neutrophiles - ic. Ca2+ release - chemotaxis - exocytosis - resp. burst - histamine release micro bl.vessels perm. incr. Characterization of IL-8 chemokine = Neutrophil activator peptide - NAP2; = Melanoma growth stimulator activity - MGSA Target cells: neutrophils, macrophages, T-Ly, mast cells, endothel, keratinocyte Homodimer (Leu25 + CH3 - blocks) Receptors Chtx. IL-8R1 4000 +++ IL-8R2 1700 + (7 loop transmembrane domain, G-prot.)

  7. Chemokine receptors

  8. RANTES receptor Ca2+ channel Cell membrane FUNCTIONAL RESPONSES Uropodium formation prot. against HIV Chemotaxis IL-2 rec. expr. Adh. mol. expr. Cytokine release Proliferation

  9. Extravasation and chemokines/receptors

  10. Extravasation - Chemokines and adhesion molecules -

  11. Extravasation - Chemokines and adhesion molecules -

  12. Steps of guiding and gradients

  13. Chemokine producer cells

  14. CXC kemokines

  15. CC chemokines

  16. Chemokine receptors and their ligand-specificity

  17. Chemokine receptors and their ligand-specificity Receptor Ligand Target cell CXCR 1 IL-8, GRO-a, NAP-2, ENA-78 neutrophil, NK-cell 2 IL-8 neutrophil, NK-cell 3 IP-10, MIG, I-TAC monocyte, T-cell 4 SDF-1 monocyte, T-cell

  18. Chemokine receptors and their ligand-specificity Receptor Ligand Target cell CCR 1 MIP-1a, RANTES, MIP-1b, monocyte, eosinophil MCP-1,-2,-3 2 MCP-1,-2,-3,-4,-5 monocyte 3 eotaxin, RANTES, MIP-1a, eosinophil, monocyte MIP-1b basophil 4 MCP-1, MIP-1a, RANTES monocyte 5 MIP-1a, MIP-1b, RANTES monocyte, T-cell 6 MIP-3b dendritic cell 7 MIP-3b act. T-cell 8 I-309 monocyte

  19. Chemokine receptors and their ligand-specificity Receptor Ligand Target cell CX3CR 1 fractalkine monocyte, act. T- cell, NK-cell Receptor Ligand Target cell DARC 1 IL-8, GRO-a, NAP-2, RBC., endothel of (Duffy Ag) ENA-78,RANTES, post capillary venules MCP-1, MCP-3 Receptor Ligand Target cell Viral rec. US28 MIP-1a, RANTES, MCP ECRF-3 IL-8, GRO-a, NAP-2

  20. Viral chemokine-binding proteins ournal of Leukocyte Biology July 1, 2002 vol. 72 no. 1 24-34

  21. Viral chemokine-binding proteins / chemokine receptors

  22. Chemotactic potential of interleukines IL-2 IL-2 < IL-8 b chain is required for migratory effect LCF (lymphocyte chemoattractant factor) acts via IL-2 receptors BUT: - two LCF monomers - expression of CD4 are required IL-3 eosinophil = neutrophil IL-5 eosinophil > neutrophil IL-6 NK killer

  23. Colony stimulating factors (~CSF) direct effect on „killing” mechanism Macrophage-CSF induced synthesis: granulocyte-CSF, g -interferon, TNF, IL-1 PGE2 inhibited mgration in neutrophils increased adhesion, margination phagocytosis, killing Granulocyte-CSF

  24. CC chemokines Monocyta chemotactic protein (MCP) Macrophag inflammatory protein (MIP) Regulated upon activation, normal T cell expressed and secreted (RANTES) Homologies Structure: MCP1- MCP2 (62%) - MCP3 (71%) Effect: - pertussis toxin blocks MCP1 and MCP3 - cholera toxin blocks MCP2 - blocking Ser/Thr kinase influences mainly chemotaxis induced by MCP2 - MCP1 and MCP3 increases i.c. Ca2+ levels

  25. Overlapping in ligands acting on CC-receptors

  26. Tricks and mimics Acetylated peptide fragment from the ECM protein collagen mimics key sequences of IL-8. The acetylated tripeptide is acPGP, it induces neutrophil chemotaxis in vitro and emigration in vivo.

  27. Regulation of integrines by chemokines

  28. Significance in basic clinical aspects

  29. Chemokines and tumors / metastasis Nature Reviews Cancer 4, 540-550 (July 2004)

  30. CC-receptors and HIV infection

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