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The chemokine receptor CCR5 has been found to play a key role in early infection with macrophage-tropic isolates of HIV-1 and CCR5 deficiency is associated with a relative resistance to HIV-1 infection. In this context, we studied the regulation of CCR5 gene expression by cytokines, and in particular, interleukin (IL)-10 in human monocytes. CCR5 mRNA was rapidly up-regulated by exposure of monocytes to graded concentrations of IL-10, with near maximal stimulation with 10 ng/ml. The effect was rapid, being detectable as early as 1 h and maximal between 2 and 4 h of treatment. Pretreatment of monocytes with actinomycin D prevented the IL-10-induced effect, suggesting a transcriptional mechanism for CCR5 up-regulation by IL-10. Protein expression of CCR5 was also enhanced by IL-10, as indicated by a 3-fold increase in anti-CCR5 antibody labeling of monocytes treated for 20 h with IL-10. Increased surface expression of CCR5 persisted at 48 h of treatment. Moreover, IL-10-treated monocytes responded with augmented intracellular Ca++ mobilization and enhanced (3-4-fold) chemotaxis in response to the CCR5 ligand MIP-1beta(25 ng/ml). Taken together, our data indicate that IL-10 can modulate CCR5 expression and function. This can constitute a potentially important regulatory mechanism which can affect not only responses during inflammation, but also susceptibility to HIV-1 infection. |
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