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-1α and tumor necrosis factor α 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 α production, associated with increased tributyltin-induced activation of transcription factor nuclear factor κB 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 κB activation and cytokine production, this being preceded by an increase in cellular oxidative activity, essential for nuclear factor κB activation, that is time and dose (0.1-10 μM) 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 phosphor-othioate 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.
Cyclosporin A exacerbates skin irritation induced by tributyltin by increasing nuclear factor κb activation / E. Corsini, B. Viviani, M. Marinovich, C.L. Galli. - In: JOURNAL OF INVESTIGATIVE DERMATOLOGY. - ISSN 0022-202X. - 117:6(2001), pp. 1627-1634.
|Titolo:||Cyclosporin A exacerbates skin irritation induced by tributyltin by increasing nuclear factor κb activation|
CORSINI, EMANUELA (Primo)
VIVIANI, BARBARA (Secondo)
MARINOVICH, MARINA (Penultimo)
GALLI, CORRADO LODOVICO (Ultimo)
|Parole Chiave:||Cyclophilin; Keratinocytes; Mitochondria; Organitans|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||2001|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1046/j.0022-202x.2001.01590.x|
|Appare nelle tipologie:||01 - Articolo su periodico|