Anti-psoriatic drug anthralin activates transcription factor NF-kappa B in murine keratinocytes.
Anthralin is one of the most effective and safest therapeutic agents for the treatment of psoriasis, a skin disease characterized by epidermal hyperproliferation and hyperkeratosis. The drug induces and inflammatory response in the skin involving the expression of cytokine and cell adhesion molecule genes that is thought to be essential for its therapeutic efficacy. Reactive oxygen intermediates (ROIs) generated in vivo during the auto-oxidation of anthralin were discussed as mediators of the inflammatory response, but it is not yet understood how this is translated into novel inflammatory gene expression. In this study, we show that at little as 10 microM anthralin can activate a prototypic form of transcription factor NF-(kappa)B, a central transcriptional regulator of inflammatory and immune responses. Two different lines of evidence show that ROIs, in particular H2O2, are second messengers for the anthralin-induced NF-(kappa)B activation. Firstly, the activation could be inhibited by the structurally unrelated antioxidants N-acetyl-L-cysteine and pyrrolidinedithiocarbamate. Secondly, keratinocytes stably overexpressing catalase showed a significant reduction of NF-(kappa)B activation, while stable overexpression of Cu/Zn-superoxide dismutase augmented the anthralin effect. Our data suggest that ROI-induced NF-(kappa)B plays a role in the anti-psoriatic activity of the drug anthralin.
Schmidt
K N
KN
Institute of Biochemistry, Albert Ludwigs University, Freiburg, Germany.
Podda
M
M
Packer
L
L
Baeuerle
P A
PA
D000287:Administration, Topical; D000818:Animals; D000875:Anthralin / Q000378:metabolism / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology*; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011565:Psoriasis / Q000188:drug therapy / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015290:Second Messenger Systems; D013482:Superoxide Dismutase / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D000875:Anthralin