Redox regulation of chemokine receptor expression

Cytokines and reactive oxygen intermediates (ROI) are frequent companions a t sites of acute inflammation. We have shown previously that in human monoc ytes, bacterial lipopolysaccharide, IL-l, and tumor necrosis factor-cy indu ce a rapid down-regulation of the monocyte chemotactic protein-1 receptor C CR2 (CC chemokine receptor-2). These stimuli also induce production of ROI, In this paper, we investigate the influence of antioxidants and/or ROI on chemokine-receptor expression. In human monocytes, the antioxidant pyrrolid ine dithiocarbamate (PDTC) rapidly inhibited CCR2 (95-100% of inhibition) a nd CCR5 (77-100% of inhibition) mRNA expression by strongly decreasing tran script stability. CCR2 half-life was decreased from 1.5 h to 45 min; CCR5 h alf-life was decreased from 2 h to 70 min. This inhibitory activity also in cluded CXCR4 (CXC chemokine receptor-4) but not CXCR2 receptor and, althoug h to a lesser extent, was shared by the antioxidants N-acetyl-L-cysteine an d 2-mercaptoethanol. In contrast, the ROI-generating system xanthine/xanthi ne oxidase increased CCR5 and CXCR4 mRNA expression and counteracted the in hibitory effect of PDTC. Accordingly, H2O2 and the glutathione-depleting dr ug buthionine sulfoximine increased to different extents CCR2, CCR5, and CX CR4 mRNA expression. The PDTC-mediated inhibition of CCR5 and CXCR4 mRNA ex pression was associated with decreased chemotactic responsiveness (>90% inh ibition) and with a marked inhibition of surface-receptor expression, In co ntrast, xanthine/xanthine oxidase opposed the bacterial lipopolysaccharide- and tumor necrosis factor-alpha-mediated inhibition of CCR5 and CXCR4 mRNA expression and increased both the CCR5 surface expression and the cell mig ration (3-fold) in response to macrophage inflammatory protein-1 beta. Thes e results suggest that the redox status of cells is a crucial determinant i n the regulation of the chemokine system.