title: TNF-alpha induction by nickel compounds is specific through ERKs/AP-1-dependent pathway in human bronchial epithelial cells.
abstract: The chronic lung inflammatory activity and carcinogenicity of nickel compounds have been well documented by previous studies from epidemiology both in vitro and in vivo. However, the molecular mechanism involved in nickel-induced chronic lung inflammation is much less understood. The current study demonstrates that exposure of human bronchial epithelial cells (Beas-2B) to nickel compounds results in the induction of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and transactivation of nuclear factor of activated T cells (NFAT), nuclear factor-kappaB (NF-kappaB), and activator protein-1 (AP-1). Further studies show that neither overexpression of IKKbeta-KM, a kinase inactive mutant of IKKbeta, nor the ectopic expression of a dominant negative mutant of NFAT could inhibit the TNF-alpha induction by nickel exposure. Overexpression of TAM67, a dominant-negative mutant of c-Jun, dramatically reduced the TNF-alpha induction, suggesting that AP-1 is a mediator of TNF-alpha induction in nickel responses. Our results show that ERKs are AP-1 upstream kinases responsible for TNF-alpha induction by nickel exposure; although JNKs, ERKs, and p38K were all activated in the Beas-2B cells exposed to nickel compounds. Our results demonstrate that inflammatory TNF-alpha could be induced by nickel exposure in Beas-2B cells specifically through an ERKs/AP-1-dependent pathway.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA. dingjin1103@hotmail.com
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.forename: Beifang
authors.initials: B
authors.lastname: Ning
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Gong
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.forename: Chang-Yan
authors.initials: CY
authors.lastname: Chen
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D001980:Bronchi / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D009532:Nickel / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D009532:Nickel; D048049:Extracellular Signal-Regulated MAP Kinases