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

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Presentation on theme: "Chemokines Dr. habil. Kőhidai, László Chemotaxis Research Group Dept. Genetics, Cell- & Immunobiology, Semmelweis University 2011."— Presentation transcript:

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. 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 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 It is possible that dimerizartion is just more thermodynamically favored

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

6 Characterization of IL-8 chemokine = Neutrophil activator peptide - NAP2; = Melanoma growth stimulator activity - MGSA Neutrophiles - ic. Ca 2+ release - chemotaxis - exocytosis - resp. burst - histamine release micro bl.vessels perm. incr. micro bl.vessels perm. incr. Homodimer (Leu25 + CH 3 - blocks) Receptors Chtx. IL-8R IL-8R (7 loop transmembrane domain, G-prot.) domain, G-prot.) Target cells: neutrophils, macrophages, T-Ly, mast cells, endothel, keratinocyte endothel, keratinocyte

7 Chemokinereceptors

8

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

10 Extravasation and chemokines/receptors

11 Extravasation - Chemokines and adhesion molecules - - Chemokines and adhesion molecules -

12 Extravasation

13 Steps of guiding and gradients

14 Chemokine producer cells

15 CXC kemokines

16 CC chemokines

17 Chemokine receptors and their ligand-specificity

18 ReceptorLigandTarget cell CXCR1IL-8, GRO-a, NAP-2, ENA-78neutrophil, NK-cell 2IL-8neutrophil, NK-cell 3IP-10, MIG, I-TACmonocyte, T-cell 4SDF-1monocyte, T-cell

19 ReceptorLigandTarget cell CCR1MIP-1a, RANTES, MIP-1b,monocyte, eosinophil MCP-1,-2,-3 2MCP-1,-2,-3,-4,-5monocyte 3eotaxin, RANTES, MIP-1a,eosinophil, monocyte MIP-1bbasophil 4MCP-1, MIP-1a, RANTESmonocyte 5MIP-1a, MIP-1b, RANTESmonocyte, T-cell 6MIP-3bdendritic cell 7MIP-3bact. T-cell 8I-309monocyte Chemokine receptors and their ligand-specificity

20 ReceptorLigandTarget cell CX 3 CR1fractalkine monocyte, act. T- cell, NK-cell ReceptorLigandTarget cell DARC1IL-8, GRO-a, NAP-2,RBC., endothel of (Duffy Ag)ENA-78,RANTES,post capillary venules MCP-1, MCP-3 MCP-1, MCP-3 ReceptorLigandTarget cell Viral rec. US28MIP-1a, RANTES, MCP US28MIP-1a, RANTES, MCP ECRF-3IL-8, GRO-a, NAP-2 ECRF-3IL-8, GRO-a, NAP-2

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

22 Viral chemokine-binding proteins / chemokine receptors

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

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

25 CC chemokines Monocyta chemotactic protein (MCP) Macrophag inflammatory protein (MIP) Regulated upon activation, normal T cell expressed and secreted (RANTES) 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 chemotaxis induced by MCP2 - MCP1 and MCP3 increases i.c. Ca 2+ levels

26 Overlapping in ligands acting on CC-receptors

27 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. Tricks and mimics

28 Regulation of integrines by chemokines

29 Significance in basic clinical aspects

30 Chemokines and tumors / metastasis Nature Reviews Cancer 4, (July 2004)

31 CC-receptors and HIV infection


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