Keratinocyte-derived chemotactic cytokines: Expressional modulation by nitric oxide in vitro and during cutaneous wound repair in vivo

Inhibition of inducible nitric oxide-synthase (iNOS) enzymatic activity dur ing cutaneous wound repair leads to severely impaired tissue regeneration. To assess whether disturbed leukocyte in filtration might participate in im paired repair, we determined expressional kinetics of neutrophil-attracting macrophage inflammatory protein-2 (MIP-2), and monocyte-attracting macroph age chemoattractant protein-1 (MCP-1) using an excisional wound healing mod el in mice. MCP-1 was induced in epithelial keratinocytes upon wounding, an d our data indicate that NO serves a negative regulatory role for MCP-1 exp ression in vivo as clearly reduced numbers of wound margin keratinocytes as sociated with NO-deficient repair compensate for high MCP-1 expression leve ls observed during normal healing. MIP-2 expression was restricted to hair follicles which were not reduced in number during NO-deficient repair. In v itro studies confirmed a regulatory role of NO for keratinocyte-derived che mokine expression, as NO attenuated IL-1 beta- and TNF-alpha-induced MCP-1 mRNA expression, whereas NO augmented IL-1 beta-induced IL-8 (functional hu man homolog to murine MIP-2) mRNA expression in the human keratinocyte cell line HaCaT, (C) 2000 Academic Press.