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Antonio Sica^*,, Alessandra Saccani^*, Alessandro Borsatti^*, Christine A. Power^||, Timothy N.C. Wells^||, Walter Luini, Nadia Polentarutti^*, Silvano Sozzani^*, and Alberto Mantovani^*,

From the ^* Istituto di Ricerche Farmacologiche "Mario Negri", 20157 Milan, Italy; Laboratory of Molecular Biology, Istituto G. Gaslini, 16148 Genova-Quarto, Italy; Section of Pathology and Immunolgy, Department of Biotechnology, University of Brescia, 25123 Italy; ^|| Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development, 1228 Plan-les-Ouates, Geneva, Switzerland.

The present study was designed to investigate the effect of bacterial lipopolysaccharide (LPS) on C–C chemokine receptors (CCR) expressed in human mononuclear phagocytes. LPS caused a rapid and drastic reduction of CCR2 mRNA levels, which binds MCP-1 and -3. CCR1 and CCR5 mRNAs were also reduced, though to a lesser extent, whereas CXCR2 was unaffected. The rate of nuclear transcription of CCR2 was not affected by LPS, whereas the mRNA half life was reduced from 1.5 h to 45 min. As expected, LPS-induced inhibition of CCR2 mRNA expression was associated with a reduction of both MCP-1 binding and chemotactic responsiveness. The capacity to inhibit CCR2 expression in monocytes was shared by other microbial agents and cytokines (inactivated Streptococci, Propionibacterium acnes, and to a lesser extent, IL-1 and TNF-). In contrast, IL-2 augmented CCR2 expression and MCP-1 itself had no effect. These results suggest that, regulation of receptor expression in addition to agonist production is likely a crucial point in the regulation of the chemokine system.

Note added in proof: During handling of this manuscript, we became aware of a study (Verani, A., G. Scarlatti, M. Comar, E. Tresoldi, S. Polo, M. Giacca, P. Lusso, A.G. Siccardi, and D. Vercelli. C–C chemokines released by LPS-stimulated human macrophages suppress HIV-1 infection in both macrophages and T cells. J. Exp. Med. In press) showing that LPS-induced chemokines may inhibit HIV infection of macrophages. Thus, inhibition of CCR2 expression and induction of chemokine production may both contribute to the observations with LPS reported in references 30 and 31.

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