• J. Am. Soc. Nephrol. · Jan 2010

    ER stress depresses NF-kappaB activation in mesangial cells through preferential induction of C/EBP beta.

    • Kunihiro Hayakawa, Shotaro Nakajima, Nobuhiko Hiramatsu, Maro Okamura, Tao Huang, Yukinori Saito, Yasuhiro Tagawa, Minori Tamai, Shuhei Takahashi, Jian Yao, and Masanori Kitamura.
    • Department of Molecular Signaling, University of Yamanashi, Shimokato 1110, Chuo, Yamanashi 409-3898, Japan.
    • J. Am. Soc. Nephrol. 2010 Jan 1;21(1):73-81.

    AbstractModest induction of endoplasmic reticulum (ER) stress confers resistance to inflammation in glomeruli. Recently, we found that ER stress leads to mesangial insensitivity to cytokine-induced activation of NF-kappaB, but the underlying mechanisms are incompletely understood. ER stress can trigger expression of CCAAT/enhancer-binding proteins (C/EBPs), which interact with transcription factors including NF-kappaB. Here, we investigated a role for C/EBPs in the ER stress-induced resistance to cytokines. Mesangial cells preferentially induced C/EBPbeta after exposure to thapsigargin or tunicamycin; induction of C/EBPdelta was modest and transient, and expression of C/EBPalpha was absent. The induction of C/EBPbeta correlated with accumulation of C/EBPbeta protein and enhanced transcriptional activity of C/EBP. Overexpression of C/EBPbeta markedly suppressed TNF-alpha-induced activation of NF-kappaB, independent of its transacting potential. Knockdown of C/EBPbeta by small interfering RNA reversed the suppressive effect of ER stress on NF-kappaB. In vivo, preconditioning of mice with ER stress induced renal C/EBPbeta and suppressed NF-kappaB-dependent gene expression in response to LPS. Using dominant negative mutants and null mutants for individual branches of the unfolded protein response, we identified the RNA-dependent protein kinase-like ER kinase (PERK) and the inositol-requiring ER-to-nucleus signal kinase 1 (IRE1) pathways as the unfolded protein response responsible for ER stress-induced C/EBPbeta. These results suggest that ER stress blunts cytokine-triggered activation of NF-kappaB, in part through PERK- and IRE1-mediated preferential induction of C/EBPbeta.

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