ULTRAVIOLET-RADIATION EFFECTS ON HUMAN KERATINOCYTE ICAM-1 EXPRESSION - UV-INDUCED INHIBITION OF CYTOKINE-INDUCED ICAM-1 MESSENGER-RNA EXPRESSION IS TRANSIENT, DIFFERENTIALLY RESTORED FOR IFN-GAMMA VERSUS TNF-ALPHA, AND FOLLOWED BY ICAM-1 INDUCTION VIA A TNF-ALPHA-LIKE PATHWAY

Human keratinocytes (KC) during the course of inflammatory dermatoses strongly express the surface molecule ICAM-1, which plays an important role in the generation of the epidermal inflammatory infiltrate by mediating leukocyte-keratinocyte interactions. Accordingly, KC ICAM-1 expression is known to be induced in vivo and in vitro by cytokines either via the TNF-alpha/TNF-beta or via the IFN-gamma-mediated pathway. In contrast, ultraviolet (UV) radiation previously has been found to potently inhibit cytokine-induced KC ICAM-1 surface expression by a sublethal mechanism. In order to further define this novel immunosuppressive effect of UV light, the effects of in vitro UV radiation on ICAM-1 mRNA expression in transformed human KC (KB cells) were examined. Accordingly, UV light(0 - 100 J/m2) inhibited IFN-gamma- as well as TNF-alpha-induced ICAM-1 mRNA expression, if KC were cytokine stimulated immediately after irradiation. After a 12-h incubation period, however, IFN-gamma responsiveness was found to be restored in irradiated cells, whereas restoration of responsiveness to TNF-alpha required at least a 24-h recovery phase. Moreover, UV light alone did not alter ICAM-1 mRNA levels after 4, 12, or 24 h. After 48 h, however, a significant increase in ICAM-1 mRNA and surface expression in UV-irradiated KC could be observed. in addition, this increase could be superinduced by stimulation of irradiated KC with IFN-gamma, but not with TNF-alpha. UV-induced upregulation of ICAM-1 expression could be mimicked by stimulating unirradiated cells with supernatants derived from UV-irradiated cells. Addition of biologically active anti-TNF-alpha antibodies to UV-irradiated cells-or to supernatants derived from UV-irradiated KC, however, did not even partially abolish this ICAM-1 - inducing activity. UV light thus seems to affect KC ICAM-1 mRNA expression in a biphasic manner: an early period of inhibition of cytokine-induced ICAM-1 expression is transient and followed by restoration of responsiveness to ICAM-1 - inducing cytokines. Moreover, UV itself is able to induce ICAM-1 mRNA expression at this later time point via a TNF-alpha-like pathway. These studies identify UV irradiation as a potent modulator of cytokine regulated ICAM-1 gene transcription with the capacity to induce both inhibitory as well as enhancing effects.