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(American Journal of Pathology. 2002;161:1409-1418.)
© 2002 American Society for Investigative Pathology

Regular Articles

Nitric Oxide Donors Suppress Chemokine Production by Keratinocytes in Vitro and in Vivo

Maria Laura Giustizieri^*, Cristina Albanesi^*, Claudia Scarponi^*, Ornella De Pità and Giampiero Girolomoni^*

From the Laboratories of Immunology^* and Allergy and Clinical Immunology, and the Second Division of Dermatology, Istituto Dermopatico dell’Immacolata, Istituto di Ricovero e Cura e Carattere Scientifico, Rome, Italy

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- and tumor necrosis factor-. 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- and tumor necrosis factor-. 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-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.

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