title: Redox regulation of chemokine receptor expression.
abstract: Cytokines and reactive oxygen intermediates (ROI) are frequent companions at sites of acute inflammation. We have shown previously that in human monocytes, bacterial lipopolysaccharide, IL-1, and tumor necrosis factor-alpha induce a rapid down-regulation of the monocyte chemotactic protein-1 receptor CCR2 (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 pyrrolidine dithiocarbamate (PDTC) rapidly inhibited CCR2 (95-100% of inhibition) and CCR5 (77-100% of inhibition) mRNA expression by strongly decreasing transcript stability. CCR2 half-life was decreased from 1.5 h to 45 min; CCR5 half-life was decreased from 2 h to 70 min. This inhibitory activity also included CXCR4 (CXC chemokine receptor-4) but not CXCR2 receptor and, although to a lesser extent, was shared by the antioxidants N-acetyl-l-cysteine and 2-mercaptoethanol. In contrast, the ROI-generating system xanthine/xanthine oxidase increased CCR5 and CXCR4 mRNA expression and counteracted the inhibitory effect of PDTC. Accordingly, H(2)O(2) and the glutathione-depleting drug buthionine sulfoximine increased to different extents CCR2, CCR5, and CXCR4 mRNA expression. The PDTC-mediated inhibition of CCR5 and CXCR4 mRNA expression was associated with decreased chemotactic responsiveness (>90% inhibition) and with a marked inhibition of surface-receptor expression. In contrast, 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 migration (3-fold) in response to macrophage inflammatory protein-1beta. These results suggest that the redox status of cells is a crucial determinant in the regulation of the chemokine system.
authors.affiliation: Istituto di Ricerche Farmacologiche "Mario Negri," via Eritrea 62, 20157 Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Saccani
authors.forename: S
authors.initials: S
authors.lastname: Saccani
authors.forename: S
authors.initials: S
authors.lastname: Orlando
authors.forename: M
authors.initials: M
authors.lastname: Sironi
authors.forename: S
authors.initials: S
authors.lastname: Bernasconi
authors.forename: P
authors.initials: P
authors.lastname: Ghezzi
authors.forename: A
authors.initials: A
authors.lastname: Mantovani
authors.forename: A
authors.initials: A
authors.lastname: Sica
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D015152:Blotting, Northern; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008623:Mercaptoethanol / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D010084:Oxidation-Reduction; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D054390:Receptors, CCR2; D054398:Receptors, CCR4; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000276:immunology / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism; D023063:Receptors, Interleukin-8B; D013859:Thiocarbamates / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000975:Antioxidants; C515334:CCR2 protein, human; C515354:CCR4 protein, human; D016166:Free Radical Scavengers; D011759:Pyrrolidines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D054390:Receptors, CCR2; D054398:Receptors, CCR4; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D023063:Receptors, Interleukin-8B; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D008623:Mercaptoethanol; D006861:Hydrogen Peroxide; D000111:Acetylcysteine