Chemokines

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Chemokines
Dr. habil. Kohidai, László Chemotaxis Research
Group Dept. Genetics, Cell- Immunobiology,
Semmelweis University 2011.
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Classification of chemokines
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Characterization of IL-8 chemokine
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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
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Receptor-ligand interaction
GAG
Signalling
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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.)
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Chemokine receptors
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Extravasation and chemokines/receptors
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Extravasation - Chemokines and adhesion
molecules -
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Extravasation - Chemokines and adhesion
molecules -
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Steps of guiding and gradients
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Chemokine producer cells
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CXC kemokines
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CC chemokines
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Chemokine receptors and their ligand-specificity
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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
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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 M
IP-1a, MIP-1b, RANTES monocyte,
T-cell 6 MIP-3b dendritic cell 7 MIP-3b
act. T-cell 8 I-309 monocyte
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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
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Viral chemokine-binding proteins
ournal of Leukocyte Biology July 1, 2002 vol.
72 no. 1 24-34
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Viral chemokine-binding proteins / chemokine
receptors
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Chemotactic potential of interleukines
IL-2 IL-2 lt 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 eosinophi
l gt neutrophil IL-6 NK killer
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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
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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
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Overlapping in ligands acting on CC-receptors
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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.
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Regulation of integrines by chemokines
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Significance in basic clinical aspects
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Chemokines and tumors / metastasis
Nature Reviews Cancer 4, 540-550 (July 2004)
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CC-receptors and HIV infection