ABSTRACT
We performed this study to determine the relationship between activation of nuclear factor (NF)-kappaB and inhibition of keratinocyte growth by anthralin, which not only might be useful for a better understanding of the role of NF-kappaB in the pathogenesis of psoriasis, but also indicate whether the inflammatory reaction induced by anthralin is inseparable from its antipsoriatic activity. The involvement of NF-kappaB was assessed using the antipsoriatic drugs leflunomide and triptolide (T0) as effectors, since they can inhibit NF-kappaB activation induced by anthralin. The results showed that the inhibition of keratinocyte growth by anthralin was not related to the activation of NF-kappaB. Using sodium salicylate, a known NF-kappaB inhibitor, further confirmed this conclusion. Thus it might be possible to inhibit the inflammatory response induced by anthralin via repression of NF-kappaB activation. We found that leflunomide or T0 could significantly inhibit the mRNA overexpression of interleukin-8 and intercellular adhesion molecule-1 in keratinocytes induced by anthralin. Taken together, our data indicate that the growth inhibition of anthralin is related to the NF-kappaB-independent signaling pathway, and that leflunomide or T0 could control proinflammatory cytokine expression induced by anthralin via inhibiting the activation of NF-kappaB.
Subject(s)
Anthralin/antagonists & inhibitors , Anti-Inflammatory Agents, Non-Steroidal/antagonists & inhibitors , Diterpenes/pharmacology , Enzyme Inhibitors/pharmacology , Immunosuppressive Agents/pharmacology , Isoxazoles/pharmacology , Keratinocytes/drug effects , NF-kappa B/antagonists & inhibitors , Phenanthrenes/pharmacology , Signal Transduction/drug effects , Anthralin/toxicity , Anti-Inflammatory Agents, Non-Steroidal/toxicity , Blotting, Western , Cell Proliferation/drug effects , Cells, Cultured , Epoxy Compounds , Humans , I-kappa B Proteins/metabolism , Intercellular Adhesion Molecule-1/biosynthesis , Interleukin-8/metabolism , Leflunomide , RNA, Messenger/biosynthesis , Reverse Transcriptase Polymerase Chain Reaction , Tetrazolium Salts , ThiazolesABSTRACT
The effect of FK506, a potent immunosuppressive agent, on 7,12-dimethylbenz[alpha]anthracene-initiated and anthralin-promoted skin tumor formation was examined in CD-1 mice. A topical application of 0.1 mumol FK506 to mouse skin 15 min prior to each anthralin treatment markedly inhibited skin tumor formation. Anthralin stimulated IL-1 alpha production in primary cultured mouse epidermal cells, and the peak IL-1 alpha level was observed at 6 h after the stimulation. Anthralin also stimulated IL-1 alpha release into culture medium. Both production and release of Il-1 alpha were markedly inhibited by FK506 (0.1 or 1 microM). FK506 (1 microM) alone neither affected IL-1 alpha production nor its release. It may be possible that the inhibition of IL-1 alpha production by FK506 is related to its anti-tumor-promoting action.
Subject(s)
Anthralin/antagonists & inhibitors , Anticarcinogenic Agents , Interleukin-1/biosynthesis , Skin Neoplasms/chemically induced , Tacrolimus/administration & dosage , Administration, Topical , Animals , Carcinogens , Female , Mice , Skin Neoplasms/metabolismABSTRACT
The retinoids all-trans-retinoic acid, 13-cis-retinoic acid, 4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1E- propen-1-yl]benzoic acid, 6-[1-(4-carboxyphenyl)-1E-propen-2-yl]-3,4-dihydro-4,4-dimethyl-2H -1-benzothiopyran, and 6-(5,6,7,8,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)- 2-naphthalenecarboxylic acid inhibited the induction of ornithine decarboxylase in CD-1 mouse epidermis treated with the weak tumor promoter anthralin (444 nmol). Enzyme activity reached maximal levels 48 h after the application of the promoter. This activity was most effectively inhibited when retinoids were applied to the epidermis 24 h after the promoter. These retinoids also inhibited the appearance of papillomas in mouse epidermis in the two-stage tumorigenesis model using 7,12-dimethylbenz(a)anthracene (200 nmol) as the initiator and anthralin (444 nmol) as the promoter during the 32-week period of promotion. Comparison of the doses of retinoids required to inhibit anthralin-induced ornithine decarboxylase by 50% and those required to inhibit anthralin-induced tumor promotion by 50% demonstrated that these values correlated.
Subject(s)
Anthralin/antagonists & inhibitors , Epidermis/enzymology , Ornithine Decarboxylase/biosynthesis , Retinoids/pharmacology , Skin Neoplasms/chemically induced , Administration, Topical , Animals , Chemical Phenomena , Chemistry , Enzyme Induction/drug effects , Female , Mice , Papilloma/chemically induced , Retinoids/administration & dosageABSTRACT
Application of 1% potassium hydroxide (KOH) reduced subsequent development of anthralin inflammation without loss of its therapeutic effect on psoriasis. Teepol had a similar but smaller effect on subsequent development of inflammation. The action of KOH appears to have resulted from enhanced oxidation of anthralin to inactive products and the action of Teepol to have increased anthralin solubility and removal. The effect of KOH and Teepol decreased with time after anthralin application and both were ineffective by 24 h, indicating that anthralin persists on the skin in an active form for up to 24 h after a single application. The reduction of anthralin inflammation without loss of therapeutic effect is potentially useful in short contact anthralin therapy.
