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 activation of plasma membrane-associated Src tyrosine kinases. These molecules then trigger a signalling cascade that results in activation of the transcription factor AP-1 which subsequently transactivates the early immediate genes including c-jun. This pathway has been postulated to play a protective role against UV damage. As aminoquinoline antimalarials such as chloroquine are known to downregulate several photoinduced cutaneous disorders including LE-specific skin disease, we asked whether 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 construct were then treated with physiologically relevant concentrations of chloroquine followed by exposure to 0-125 J/m2 of UV-B from a bank of unfiltered FS20 lamps. Chloroquine pretreatment resulted in a dose-dependent increase in luciferase activity in permanently transfected A431 cells (luciferase activity was increased by 45% at 2.5 x 10(-5) M chloroquine and 125 J/m2 of UV-B). Hydroxychloroquine pretreatment also resulted in an increase in luciferase activity. Primaquine, an 8-aminoquinoline, did not influence the UV-B induced c-jun activity. Furthermore, chloroquine did not have a similar impact on HSP-70 gene activity during heat shock. These studies suggest that the beneficial effect of the 4-aminoquinoline antimalarials in various photodermatoses including cutaneous LE might result in part from the capacity of these drugs to enhance the protective early limb of the UV response.
Nguyen
T Q
TQ
Department of Dermatology, University of Texas Southwestern Medical Center, Dallas 75235, USA.
Capra
J D
JD
Sontheimer
R D
RD
D000634:Aminoquinolines / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D015533:Transcriptional Activation / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D014162:Transfection / Q000235:genetics; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D000634:Aminoquinolines; D000962:Antimalarials; D016755:Proto-Oncogene Proteins c-jun; D011994:Recombinant Proteins; D002738:Chloroquine; C001920:4-aminoquinoline