Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10817066 | Cellular Signalling | 2005 | 17 Pages |
Abstract
IFN-γ and TNF-α are major proinflammatory cytokines implicated in islet β-cell destruction, which results in type-1 diabetes; however, the underlying mechanism is not clear. Using pancreatic β-cell line MIN6N8 cells, co-treatment with TNF-α and IFN-γ, but neither cytokine alone, synergistically induced apoptosis, correlated with the activation of the JNK/SAPK, which resulted in the production of reactive oxidative species (ROS) and loss of mitochondrial transmembrane potential (ÎΨm). Additionally, cells transfected with wild-type JNK1 became more susceptible to apoptosis induced by TNF-α/IFN-γ through ROS production and loss of ÎÏm, while cascading apoptotic events were prevented in dominant-negative JNK1-transfected or JNK inhibitor SP600125-treated cells. As the antioxidant, N-acetyl-cysteine, failed to completely suppress apoptosis induced by TNF-α/IFN-γ, an additional pathway was considered to be involved. The level of p53 was significantly increased through synergistic activation of JNK by TNF-α/IFN-γ. Furthermore, the synergistic effect of TNF-α/IFN-γ on apoptosis and ROS production was further potentiated by the overexpression of wild-type p53, but not with mutant p53. This synergistic activation of JNK/SAPK by TNF-α/IFN-γ was also induced in insulin-expressing pancreatic islet cells, and increased ROS production and p53 level, which was significantly inhibited by SP600125. Collectively, these data demonstrate that TNF-α/IFN-γ synergistically activates JNK/SAPK, playing an important role in promoting apoptosis of pancreatic β-cell via activation of p53 pathway together with ROS.
Keywords
PMSFBMHVDACPARPBismaleimidohexaneΔΨmN-acetyl-l-cysteineDCFH-DANACFACSfluorescent-activated cell sorter3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromideJNK/SAPKMTTROSTUNELApoptosisdichlorodihydrofluorescein diacetateislet cellsCytokinesphenylmethylsulfonyl fluorideterminal deoxynucleotidyl transferase-mediated dUTP nick-end labelingMitochondrial transmembrane potentialpoly(ADP-ribose)polymeraseReactive oxygen species
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Authors
Won Ho Kim, June Woo Lee, Bin Gao, Myeong Ho Jung,