RETINOIC ACID AFFECTS THE EXPRESSION RATE OF THE DIFFERENTIATION-RELATED GENES ARYL-HYDROCARBON RECEPTOR, ARNT AND KERATIN-4 IN PROLIFERATIVE KERATINOCYTES ONLY

The environmental contaminant dioxin exerts most of its effects by act ivating the aryl hydrocarbon receptor (AhR). The AhR is considered to play not only a role in the regulation of xenobiotic metabolism, but a lso for development, growth, and differentiation. The transcript level s of the AhR and its associated translocator protein (ARNT) were found to increase with ongoing differentiation in the human keratinocyte ce ll line HaCaT. Correspondingly, in situ hybridization studies in norma l human skin revealed an absence of AhR-expression in proliferating ba sal cells and increasing transcript levels in upper cell layers, in de pendence of keratinocyte differentiation. AhR expression in differenti ation-deficient hyperproliferative psoriatic skin was markedly decreas ed. When keratinocytes were continuously treated with 1 mu M retinoic acid (RA), the upregulation of AhR- and ARNT-mRNA levels was inhibited as was keratin 4-expression, a marker of HaCaT-keratinocyte different iation. In contrast, treatment of already differentiated cells with RA did not down-regulate these transcript levels. The mRNA levels of the prevalent retinoic acid receptors in keratinocytes, RAR gamma and RXR alpha, were not influenced by the process of differentiation or by ad dition of RA. Our data suggest that the regulation of AhR-, ARNT- and keratin 4-expression by RA is indirect and mediated by a yet to be ide ntified factor.