Cyclosporin A exacerbates skin irritation induced by tributyltin by increasing nuclear factor kappa B activation.
In searching for pharmacologic agents able to reduce xenobiotic-induced skin irritation, we found that cyclosporine A exacerbates the skin irritation induced by tributyltin. We previously demonstrated the involvement of interleukin-1 alpha and tumor necrosis factor alpha in tributyltin-induced skin irritation. Here, we show that cyclosporine A (28 mg per kg), at a dose that results in systemic immunosuppression, potentiates tributyltin-induced skin irritation through increased tumor necrosis factor alpha production, associated with increased tributyltin-induced activation of transcription factor nuclear factor kappa B in cyclosporine-A-treated mice. On the other hand, under the same experimental conditions, cyclosporine A prevented the elicitation phase of oxazolone-induced contact allergy, but was ineffective in preventing benzalkonium-chloride-induced skin irritation. Using a murine keratinocyte cell line (HEL30) we demonstrated, also in vitro, that the cyclosporine A potentiates tributyltin-induced nuclear factor kappa B activation and cytokine production, this being preceded by an increase in cellular oxidative activity, essential for nuclear factor kappa B activation, that is time and dose (0.1-10 microM) dependent. This effect was not exclusive to tributyltin but could be extended to other mitochondrial poisons such as sodium arsenate. It has been reported that cyclosporine A binds to cyclophilins. An 18-mer antisense phosphorothioate oligodeoxynucleotide was used to target mitochondrial cyclophilin D mRNA. After 24 h exposure to the oligonucleotide, the amount of cyclophilin D in the cells was decreased by 54% as judged by Western blot analysis. Cyclophilin D suppression prevented cyclosporine A potentiation of tributyltin-induced cellular oxidative activity, indicating the key role of the binding of cyclosporine A to mitochondrial cyclophilin D in mediating this effect.
Corsini
E
E
Center for Cosmetic Toxicology, Department of Pharmacological Sciences, Faculty of Pharmacy, University of Milan, Milan, Italy. emanuela.corsini@unimi.it
Viviani
B
B
Marinovich
M
M
Galli
C L
CL
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D001548:Benzalkonium Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D017449:Dermatitis, Allergic Contact / Q000378:metabolism / Q000517:prevention & control; D017453:Dermatitis, Irritant / Q000378:metabolism*; D003879:Dermatologic Agents / Q000494:pharmacology*; D005260:Female; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010081:Oxazolone / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D014220:Trialkyltin Compounds / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000891:Anti-Infective Agents, Local; D001548:Benzalkonium Compounds; D000081406:Peptidyl-Prolyl Isomerase F; D003879:Dermatologic Agents; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; C000631446:PPIF protein, mouse; D017382:Reactive Oxygen Species; D014220:Trialkyltin Compounds; D014409:Tumor Necrosis Factor-alpha; D010081:Oxazolone; C011559:tributyltin; D016572:Cyclosporine; D021983:Cyclophilins