Interaction between the CCR5 chemokine receptors and microbial HSP70.
Evidence is presented that the microbial 70-kD heat shock protein (HSP70) binds to CCR5 chemokine receptors in CCR5-transfected cell lines and in primary human cells. Significant CCR5-mediated calcium mobilization was stimulated by HSP70 and inhibited with TAK 779, which is a specific CCR5 antagonist. HSP70-mediated activation of the p38 MAPK phosphorylation signaling pathway was also demonstrated in CCR5-transfected HEK 293 cells. Direct binding of three extracellular peptides of CCR5 to HSP70 was demonstrated by surface plasmon resonance. Functional evidence of an interaction between HSP70, CCR5 and CD40 was shown by enhanced production of CCL5 by HEK 293 cells transfected with both CD40 and CCR5. Primary monocyte-derived immature DC stimulated with HSP70 produced IL-12 p40, which showed dose-dependent inhibition of >90% on treatment with both TAK 779 and anti-CD40 mAb. Stimulation of IL-12 p40 or TNF-alpha by HSP70 was related to the differential cell surface expression of CCR5 in primary human immature and mature DC, and those with the homozygous triangle DeltaDelta32 CCR5 mutation. These findings may be of significance in the interaction between HSP70 and immune responses of CCR5+ T cells in HIV-1 infection, as well as in inflammatory bowel disease.
Whittall
Trevor
T
Mucosal Immunology Unit, King's College London at Guy's and St. Thomas' Hospitals, London, UK.
Wang
Yufei
Y
Younson
Justine
J
Kelly
Charles
C
Bergmeier
Lesley
L
Peters
Barry
B
Singh
Mahavir
M
Lehner
Thomas
T
D000577:Amides / Q000494:pharmacology; D015153:Blotting, Western; D019013:CD40 Antigens / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D004797:Enzyme-Linked Immunosorbent Assay; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000276:immunology* / Q000378:metabolism; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000577:Amides; D019013:CD40 Antigens; D018840:HSP70 Heat-Shock Proteins; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; C119369:TAK 779; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium