ANTIONCOGENE P53 AND MITOGENIC CYTOKINE INTERLEUKIN-8 ABERRANTLY EXPRESSED IN PSORIATIC SKIN ARE INVERSELY REGULATED BY THE ANTIPSORIATIC DRUG TACROLIMUS (FK506)

Uncontrolled proliferation of epidermal cells is the most prominent ch aracteristic of psoriasis. This widespread skin disease can be effecti vely treated with the microbial substance FK506, which acts by modulat ing gene expression. We, therefore, asked if the drug changes the expr ession of genes involved in growth regulation (the mitogenic cytokine interleukin-8 (IL-8) and p53, a negative cell cycle regulator) and sig nal transduction (protooncogenes c-ras, c-raf, and HER-2). Gene expres sion was monitored by semiquantitative mRNA-PCR and for p53 by immunoc ytochemistry in cultured primary keratinocytes (KC). In addition, p53 expression was analysed in skin biopsies of psoriatic patients. After 1-3 hr, IL-8 mRNA levels were dose-dependently decreased in tacrolimus (FK506)-treated cells. Protooncogene expression was not significantly altered. Interestingly, p53 transcription was clearly induced by FK50 6 treatment. This tendency could be Verified on the protein level by i mmunocytochemistry. In contrast, p53 expression was decreased in lesio nal psoriatic as compared to normal skin, providing evidence that not only posttranslational modification of the p53 protein, but also trans criptional modulation of the p53 gene, are involved in pathological pr ocesses and pharmacological drug action in skin. Together with earlier results showing downmodulation for IL-8 receptor type A expression in cultured KC treated with FK506, these results suggest that both the m itogenic IL-8/IL-8R system and the cell cycle inhibitor p53 represent. potential targets for the antipsoriatic action of the drug, whereas p rotooncogenes acting downstream in mitogenic signal transduction casca des are unaffected. The differential modulation of an entire set of ge nes provides evidence for the specificity of the drug effects and rule s out nonspecific toxic effects on KC.