title: Nitric oxide donors suppress chemokine production by keratinocytes in vitro and in vivo.
abstract: Nitric oxide (NO) is involved in the modulation of inflammatory responses. In psoriatic skin, NO is highly produced by epidermal keratinocytes in response to interferon-gamma and tumor necrosis factor-alpha. In this study, we investigated whether the NO donors, S-nitrosoglutathione (GS-NO) and NOR-1, could regulate chemokine production by human keratinocytes activated with interferon-gamma and tumor necrosis factor-alpha. In addition, we studied the effects of the topical application of a GS-NO ointment on chemokine expression in lesional psoriatic skin. NO donors diminished in a dose-dependent manner and at both mRNA and protein levels the IP-10, RANTES, and MCP-1 expression in keratinocytes cultured from healthy patients and psoriatic patients. In contrast, constitutive and induced interleukin-8 production was unchanged. GS-NO-treated psoriatic skin showed reduction of IP-10, RANTES, and MCP-1, but not interleukin-8 expression by keratinocytes. Moreover, the number of CD14(+) and CD3(+) cells infiltrating the epidermis and papillary dermis diminished significantly. NO donors also down-regulated ICAM-1 protein expression without affecting mRNA accumulation in vitro, and suppressed keratinocyte ICAM-1 in vivo. Finally, NO donors inhibited nuclear factor-kappa B and STAT-1, but not AP-1 activities in transiently transfected keratinocytes. These results define NO donors as negative regulators of chemokine production by keratinocytes.
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000235:genetics; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D018946:Chemokine CCL5 / Q000235:genetics; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009824:Ointments; D011565:Psoriasis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D018950:Lipopolysaccharide Receptors; D020030:Nitric Oxide Donors; D009824:Ointments; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma