Selective inhibition of expression of the chemokine receptor CCR2 in human monocytes by IFN-gamma.
IFN-gamma is a potent activator of mononuclear phagocyte function and promotes the development of Th1 responses. Moreover, it induces and modulates chemokine production in a variety of cell types, including mononuclear phagocytes. In the present study, we examined the effect of IFN-gamma on the expression of CC chemokine receptors in human monocytes. IFN-gamma selectively and rapidly inhibited expression of the monocyte chemotactic protein (MCP) receptor CCR2 with an ED50 of approximately 50 U/ml. The effect was rapid (detectable after 1 h) and reversible. Other chemokine receptors (CCR1, CCR3, CCR4, and CCR5) were not substantially affected, and CXCR4 was reduced. IFN-gamma acted in concert with LPS, TNF-alpha, and IL-1beta in inhibiting CCR2 expression. IFN-gamma-treated monocytes showed a shorter half-life of CCR2 mRNA compared with untreated cells, whereas the rate of nuclear transcription was unaffected. The inhibition of CCR2 mRNA expression by IFN-gamma was associated with a lower number of surface receptors and lower chemotactic responsiveness. Thus, IFN-gamma, an inducer of MCP-1 and MCP-3 in mononuclear phagocytes, selectively inhibits expression of the MCP receptor CCR2 in monocytes. These results are consistent with an emerging paradigm of divergent regulation by several agents of chemokine production and receptor expression in monocytes. The inhibition of MCP-1R expression may serve as a means of retaining mononuclear phagocytes at sites of inflammation and as a feedback mechanism in the regulation of recruitment from the blood.
Penton-Rol
G
G
Department of Immunology and Cell Biology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Polentarutti
N
N
Luini
W
W
Borsatti
A
A
Mancinelli
R
R
Sica
A
A
Sozzani
S
S
Mantovani
A
A
D018932:Chemokine CCL2 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D015536:Down-Regulation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics*; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C515334:CCR2 protein, human; D018932:Chemokine CCL2; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma