4-AMINOQUINOLINE ANTIMALARIALS ENHANCE UV-B INDUCED C-JUN TRANSCRIPTIONAL ACTIVATION

Previous work has documented that the earliest observable response in mammalian cells following ultraviolet (UV) irradiation is the activati on of plasma membrane-associated Src tyrosine kinases. These molecules then trigger a signalling cascade that results in activation of the t ranscription factor AP-1 which subsequently transactivates the early i mmediate genes including c-jun. This pathway has been postulated to pl ay a protective role against UV damage. As aminoquinoline antimalarial s such as chloroquine are known to downregulate several photoinduced c utaneous disorders including LE-specific skin disease, we asked whethe r chloroquine might be capable of modulating this early limb of the UV light response. A431 cells (a human epidermal keratinocyte cell line) that had been transfected with a c-jun luciferase reporter gene const ruct were then treated with physiologically relevant concentrations of chloroquine followed by exposure to 0-125 J/m(2) of UV-B from a bank of unfiltered FS20 lamps. Chloroquine pretreatment resulted in a dose- dependent increase in luciferase activity in permanently transfected A 431 cells (luciferase activity was increased by 45% at 2.5 x 10(-5) M chloroquine and 125 J/m(2) of UV-B). Hydroxychloroquine pretreatment a lso resulted in an increase in luciferase activity. Primaquine, an 8-a minoquinoline, did not influence the UV-B induced c-jun activity. Furt hermore, chloroquine did not have a similar impact on HSP-70 gene acti vity during heat shock. These studies suggest that the beneficial effe ct of the 4-aminoquinoline antimalarials in various photodermatoses in cluding cutaneous LE might result in part from the capacity of these d rugs to enhance the protective early limb of the UV response.