title: Nrf-2 regulates cyclosporine-stimulated HO-1 expression in gingiva.
abstract: Cyclosporine-A (CsA) stimulates heme oxygenase-1 (HO-1) expression in the gingiva, but the regulation and the role of HO-1 in gingival overgrowth are not well-understood. HO-1 is regulated by several transcription factors, such as nuclear factor-κB (NF-κB) and nuclear factor erythroid-2-related factor 2 (Nrf-2). The aim of this study was to examine the role of Nrf-2 in the regulation of CsA-stimulated HO-1 expression in human gingival fibroblasts. Nrf-2 siRNA (siNrf-2), NF-κB, kinase inhibitors, and sulforaphane (SFN) were used to examine the nuclear translocation of Nrf-2 and expression of HO-1 and transforming growth factor-β1 (TGF-β1) in cells. Treatment with siNrf-2, but not with an NF-κB inhibitor, reduced CsA-stimulated HO-1 mRNA expression. ERK inhibition significantly decreased CsA-stimulated Nrf-2 nuclear translocation and HO-1 mRNA expression. Pre-treatment with SFN showed that HO-1 plays a role in attenuating CsA-mediated TGF-β1 expressions. These findings suggest that CsA-stimulated HO-1 expression is mediated through the activation of ERK, and that Nrf-2 plays a protective role against CsA-induced gingival fibrosis by modulating collagen turnover-related genes.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Y-T
authors.initials: YT
authors.lastname: Chin
authors.forename: Y-W
authors.initials: YW
authors.lastname: Liao
authors.forename: M M J
authors.initials: MM
authors.lastname: Fu
authors.forename: H-P
authors.initials: HP
authors.lastname: Tu
authors.forename: E-C
authors.initials: EC
authors.lastname: Shen
authors.forename: S
authors.initials: S
authors.lastname: Nieh
authors.forename: K-C
authors.initials: KC
authors.lastname: Shih
authors.forename: E
authors.initials: E
authors.lastname: Fu
mesh_terms: D021581:Active Transport, Cell Nucleus; D000704:Analysis of Variance; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D055786:Gene Knockout Techniques; D005881:Gingiva / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019214:Gingival Overgrowth / Q000139:chemically induced / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D017879:Isothiocyanates; D020935:MAP Kinase Signaling System; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D018709:Statistics, Nonparametric; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation
chemical_list: D024042:Collagen Type I; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D013454:Sulfoxides; D013861:Thiocyanates; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine; D051547:Heme Oxygenase-1; D048049:Extracellular Signal-Regulated MAP Kinases; C016766:sulforaphane