PUVA INHIBITS DNA-REPLICATION, BUT NOT GENE-TRANSCRIPTION AT NONLETHAL DOSAGES

The combination of psoralens and UVA radiation (PUVA photochemotherapy ) is an established treatment for many skin disorders. UVA-induced pso ralen-DNA interactions are assumed to contribute to the cutaneous anti -inflammatory and anti-proliferative effects of PUVA. PUVA-induced DNA modifications might interfere not only with DNA replication, but also with gene transcription of proinflammatory genes. We therefore studie d the effect of PUVA on cell proliferation and on the transcription of the c-jun and intercellular adhesion molecule-1 genes in a promyelocy tic (HL60) and a keratinocyte (HaCaT) cell line. PUVA inhibited cell p roliferation increasingly with increasing 8-methoxypsoralen concentrat ions or WA doses. The inhibition was observed at conditions not affect ing cell viability up to 48 h after PUVA. In contrast, PUVA did not in hibit gene transcription at anti-proliferative, yet nonlethal conditio ns. Baseline and phorbol-ester induced c-jun mRNA expression was not i nhibited, nor was baseline and IFN-gamma or phorbol-ester induced inte rcellular adhesion molecule-1 mRNA expression. In order to assess poss ible transcriptional effects of PUVA-generated reactive oxygen interme diates, the reactive oxygen intermediates-sensitive transcription fact or nuclear factor KB was assayed in mobility shift experiments. Nuclea r factor KB-specific binding activity was not induced 1-24 h after PUV A in extracts from PUVA-treated cells when compared with controls, whe reas the pro-oxidant cytokine TNF-a caused a marked increase in nuclea r factor KB binding. The presented data suggest that PUVA inhibits cel l proliferation, but not transcription, at nonlethal PUVA conditions. Furthermore, the data do not support a major role for PUVA-generated r eactive oxygen intermediates in the regulation of gene transcription.