ANTHRALIN STIMULATES KERATINOCYTE-DERIVED PROINFLAMMATORY CYTOKINES VIA GENERATION OF REACTIVE OXYGEN SPECIES

Objective and Design: Topical application of anthralin, used in the tr eatment of psoriasis, is often accompanied by severe skin inflammation , presumably due to free radical products of the drug. The role of inf lammatory cytokines and their induction by anthralin-derived reactive oxygen species were studied in cultures of normal human keratinocytes (NHKs). Materials and Methods: Anthralin was added to cultures of NHKs in the presence or absence of various antioxidants, including superox ide dismutase, tetramethylthiourea, N-acetylcysteine and vitamin E and relative changes in cytokine secretion and in the number of mRNA tran scripts were examined. In addition, NHKs were either treated with neut ralizing antibodies to tumor necrosis factor (TNF)-alpha or transfecte d with a CAT-linked IL-8 promoter to establish the direct effects of a nthralin on chemokine synthesis. Results: Anthralin, at concentrations between 5 mu M and 25 mu M, caused a marked increase in granulocyte m acrophage-colony stimulating factor (GM-CSF), interleukin (IL)-6, IL-8 and TNF alpha synthesis that was selectively inhibited by specific an tioxidants. Furthermore, anthralin induced chemokine secretion without the need of primary cytokines. Conclusions: Taken together, these stu dies suggest that oxygen radicals generated from anthralin are respons ible for the induction of inflammatory cytokines which, in turn contri butes to their dermal toxicity.