CD23-MEDIATED NITRIC-OXIDE SYNTHASE PATHWAY INDUCTION IN HUMAN KERATINOCYTES IS INHIBITED BY RETINOIC ACID-DERIVATIVES

Retinoids exert various functions including anti-proliferative and ant i-inflammatory effects on many cell types including keratinocytes and are widely used in skin diseases, such as psoriasis and acne. We have previously shown that human keratinocytes express low affinity immunog lobulin E receptor (Fc epsilon RII/CD23) when stimulated with interleu kin-4. Immunoglobulin E ligates CD23 and induces the production of nit rites (reflecting the mobilization of the nitric oxide [NO]-pathway) a nd tumor necrosis factor-alpha by human keratinocytes. Here, 13-cis an d all-trans retinoic acid (RA) were shown to reduce the production of nitrites by immunoglobulin E-activated keratinocytes by 80% in a time- and concentration-dependent fashion, As a consequence, RA derivatives also reduced the production of tumor necrosis factor-alpha by these c ells by 70%, The level of inducible NO synthase activity in activated human keratinocytes was significantly decreased upon treatment of the cells with RA derivatives (inhibition by 60% of the mean inducible NO synthase activity with 13-cis RA, 2 mu M). Treatment for 24 h with RA derivatives almost completely abolished transcription of inducible NO synthase-specific mRNA in activated keratinocytes. Therefore, RA deriv atives downregulate tumor necrosis factor-alpha release and the NO-tra nsduction pathway through the inhibition of inducible NO synthase tran scription. Together, our data provide evidence for inhibition of the N O-pathway by 13-cis and all-trans retinoic acid on CD23-activated huma n keratinocytes. These data may clarify the mechanism of the anti-infl ammatory activity of RA derivatives in skin diseases.