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.