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Up-Regulation of CCR2 Chemokine Receptor Expression and Increased Susceptibility to the Multitropic HIV Strain 89.6 in Monocytes Exposed to Glucocorticoid Hormones¹

Giselle Penton-Rol^2,*, Manuela Cota^2,, Nadia Polentarutti^*, Walter Luini^*, Sergio Bernasconi^*, Alessandro Borsatti^*, Antonio Sica^*, Gregory J. LaRosa, Silvano Sozzani^*, Guido Poli and Alberto Mantovani^3,*,§

^* Department of Immunology and Cell Biology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; AIDS Immunopathogenesis Unit, Ospedale S. Raffaele, Milan, Italy; Receptor Pharmacology, LeukoSite, Inc., Cambridge, MA 02142; and ^§ Section of Pathology and Immunology, Department of Biotechnology, University of Brescia, Brescia, Italy

Glucocorticoid hormones (GC) are potent antiinflammatory agents widely used in the treatment of diverse human diseases. The present study was aimed at assessing the effect of GC on chemokine receptor expression in human monocytes. Dexamethasone (Dex) up-regulated mRNA expression of the monocyte chemotactic protein (MCP-1, CCL2) chemokine receptor CCR2. The effect was selective in that other chemokine receptors were not substantially affected. Stimulation by Dex was observed after 4 h of exposure at concentrations of 10^-7 to 10^-5 M. Steroids devoid of GC activity were inactive, and the GC receptor antagonist, RU486, inhibited stimulation. Dex did not affect the rate of nuclear transcription, but augmented the CCR2 mRNA half-life. Augmentation of CCR2 expression by Dex was associated with increased chemotaxis. Finally, Dex treatment induced productive replication of the HIV strain 89.6, which utilizes CCR2 as entry coreceptor, in freshly isolated monocytes. Together with previous findings, these results indicate that at least certain pro- and antiinflammatory molecules have reciprocal and divergent effects on expression of a major monocyte chemoattractant, MCP-1, and of its receptor (CCR2). Augmentation of monocyte CCR2 expression may underlie unexplained in vivo effects of GC as well as some of their actions on HIV infection.

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