Membrane incorporation of 22-hydroxycholesterol inhibits chemokine receptor activity.
Cell membrane exposure to oxysterols, such as 22-hydroxycholesterol (22-OHC), has previously been shown to induce a suppressive effect on lymphocyte activation. Based on our previous findings that chemokine binding was significantly inhibited by the extraction of membrane cholesterol, we sought to assess the effects of 22-OHC treatment on chemokine ligand-binding and receptor activity. Our results revealed that 22-OHC, but not nonoxidized cholesterol, significantly reduced the binding of both SDF-1alpha and MIP-1beta to human T-cell lines and PBMCs within 1 h of treatment. Incubating the treated cells at 37 degrees C for 1 h reversed a majority of the inhibitory effects on chemokine binding. 22-OHC also inhibited intracellular calcium mobilization and cell migration in response to SDF-1alpha treatment. Interestingly, while the presence of oxysterols in cell membranes significantly inhibits chemokine receptor function, this inhibitory effect does not involve alterations in receptor conformation, expression, or a direct antagonism of chemokine binding. We propose here a novel mechanism for oxysterol-mediated inhibition of chemokine receptor function and the implications for the presence of oxysterols on immune cells.
Nguyen
Dzung H
DH
Laboratory of Immunology, National Institute on Aging, NIH, Intramural Research Program, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825, USA.
Taub
Dennis D
DD
D000911:Antibodies, Monoclonal / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D054407:Chemokine CCL4; D054377:Chemokine CXCL12; D018925:Chemokines / Q000378:metabolism / Q000494:pharmacology; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D002784:Cholesterol / Q000494:pharmacology; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism / Q000494:pharmacology*; D019169:Jurkat Cells; D007700:Kinetics; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D000911:Antibodies, Monoclonal; C515255:CXCL12 protein, human; D054407:Chemokine CCL4; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; D006888:Hydroxycholesterols; D019402:Macrophage Inflammatory Proteins; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; C003585:22-hydroxycholesterol; D002784:Cholesterol; D002118:Calcium