Anthralin stimulates keratinocyte-derived proinflammatory cytokines via generation of reactive oxygen species.
OBJECTIVE
Topical application of anthralin, used in the treatment of psoriasis, is often accompanied by severe skin inflammation, presumably due to free radical products of the drug. The role of inflammatory cytokines and their induction by anthralin-derived reactive oxygen species were studied in cultures of normal human keratinocytes (NHKs).


METHODS
Anthralin was added to cultures of NHKs in the presence or absence of various antioxidants, including superoxide dismutase, tetramethylthiourea, N-acetylcysteine and vitamin E and relative changes in cytokine secretion and in the number of mRNA transcripts were examined. In addition, NHKs were either treated with neutralizing antibodies to tumor necrosis factor (TNF)-alpha or transfected with a CAT-linked IL-8 promoter to establish the direct effects of anthralin on chemokine synthesis.


RESULTS
Anthralin, at concentrations between 5 microM and 25 microM, caused a marked increase in granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-6, IL-8 and TNFalpha synthesis that was selectively inhibited by specific antioxidants. Furthermore, anthralin induced chemokine secretion without the need of primary cytokines.


CONCLUSIONS
Taken together, these studies suggest that oxygen radicals generated from anthralin are responsible for the induction of inflammatory cytokines which, in turn contributes to their dermal toxicity.
Lange
R W
RW
Environmental Immunology Section, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA. lange+@pitt.edu
Hayden
P J
PJ
Chignell
C F
CF
Luster
M I
MI
D000111:Acetylcysteine / Q000494:pharmacology; D000287:Administration, Topical; D000875:Anthralin / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000906:Antibodies / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014810:Vitamin E / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D000906:Antibodies; D000975:Antioxidants; D016207:Cytokines; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D014810:Vitamin E; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013482:Superoxide Dismutase; D013890:Thiourea; C019107:tetramethylthiourea; D000875:Anthralin; D000111:Acetylcysteine