Rw. Lange et al., ANTHRALIN STIMULATES KERATINOCYTE-DERIVED PROINFLAMMATORY CYTOKINES VIA GENERATION OF REACTIVE OXYGEN SPECIES, Inflammation research, 47(4), 1998, pp. 174-181
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.