title: Celastrol induces expression of heme oxygenase-1 through ROS/Nrf2/ARE signaling in the HaCaT cells.
abstract: We previously demonstrated that celastrol, a quinone methide triterpenoid derived from the medicinal plant Tripterygium wilfordii, exerts its anti-inflammatory activity through up-regulation of heme oxygenase-1 (HO-1) expression in the keratinocytes. In this study, we examined the signaling pathways that lead to the up-regulation of HO-1 expression by celastrol. In HaCaT cells, celastrol-induced HO-1 expression was dependent on ROS generation. ERK and p38 MAPK were major MAPK pathways responsible for celastrol-induced HO-1 expression. Celastrol induced Nrf2 activation. Nrf2 knockdown using small interfering RNA (siRNA) inhibited celastrol-induced HO-1 expression. Treatment with celastrol resulted in a marked increase in antioxidant response element (ARE)-driven transcriptional activity, which was dependent on ROS generation and activation of ERK and p38 MAPK. Furthermore, Nrf2 siRNA significantly reversed the inhibitory effect of celastrol on IFN-γ-induced expression of ICAM-1 in the keratinocytes. Taken together, our results indicate that celastrol can activate the ROS-ERK/p38-Nrf2-ARE signaling cascades leading to the up-regulation of HO-1 which is partly responsible for its anti-inflammatory activity in the keratinocytes.
authors.affiliation: Department of Biomedical Science and Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 200-702, Republic of Korea.
authors.forename: Won Yong
authors.initials: WY
authors.lastname: Seo
authors.forename: Ah Ra
authors.initials: AR
authors.lastname: Goh
authors.forename: Sung Mi
authors.initials: SM
authors.lastname: Ju
authors.forename: Ha Yong
authors.initials: HY
authors.lastname: Song
authors.forename: Dong-Joo
authors.initials: DJ
authors.lastname: Kwon
authors.forename: Jong-Gab
authors.initials: JG
authors.lastname: Jun
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Kim
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
authors.forename: Jinseu
authors.initials: J
authors.lastname: Park
mesh_terms: D000217:Acyltransferases / Q000378:metabolism*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007371:Interferon-gamma / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D014315:Triterpenes / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species; D014315:Triterpenes; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D051547:Heme Oxygenase-1; D000217:Acyltransferases; C057250:acyl-CoA-independent retinyl ester synthetase; C050414:celastrol