A PROINFLAMMATORY ACTIVITY OF INTERLEUKIN-8 IN HUMAN SKIN - EXPRESSION OF THE INDUCIBLE NITRIC-OXIDE SYNTHASE IN PSORIATIC LESIONS AND CULTURED KERATINOCYTES

Psoriasis is a common chronic skin disease mediated by cellular immune mechanisms and characterized by an intense neutrophil cell infiltrate and proliferative activation of epidermal keratinocytes. We have prev iously described the expression of the inducible nitric oxide synthase (iNOS) in epidermal keratinocytes of psoriatic skin lesions. In this study, the role of iNOS in psoriatic inflammation was explored ex vivo in psoriatic skin biopsies and in vitro in primary cultures of human keratinocytes. Messenger RNA for the iNOS enzyme (iNOS mRNA) was detec ted by reverse transcriptase polymerase chain reaction in skin biopsie s fi-om patients with psoriasis, but not in skin specimens from patien ts with atopic eczema or from healthy volunteers. As demonstrated by i n situ hybridization and immunohistochemistry, expression of iNOS mRNA and its gene product was localized to the epidermal keratinocytes of psoriatic skin lesions. In situ hybridization further revealed a compl ete colocalization of mRNA expression for iNOS with interleukin (IL) 8 receptor-specific mRNA either in the basal germinative cell layer or at focal sites of ongoing neutrophil inflammation in suprabasal cell l ayers. Because psoriatic keratinocytes have previously been shown to e xpress mRNA transcripts for IL-8, it seemed reasonable to hypothesize that iNOS expression could be induced in an autocrine loop by IL-8. Th is hypothesis was substantiated by our in vitro experiments showing th at a combination of IL-8 and interferon gamma induces the expression o f iNOS-specific mRNA and of the functional enzyme in cultured human ke ratinocytes. These results suggest an important role for iNOS in conce rt with IL-8 and its receptor early during the formation of psoriatic lesions.