ER Stress Depresses NF-kappa B Activation in Mesangial Cells through Preferential Induction of C/EBP beta

作者：Hayakawa Kunihiro; Nakajima Shotaro; Hiramatsu Nobuhiko; Okamura Maro; Huang Tao; Saito Yukinori; Tagawa Yasuhiro; Tamai Minori; Takahashi Shuhei; Yao Jian; Kitamura Masanori^*

来源：Journal of the American Society of Nephrology, 2010, 21(1): 73-81.

DOI：10.1681/ASN.2009040432

Modest 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-kappa B, 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-kappa B. Here, we investigated a role for C/EBPs in the ER stress-induced resistance to cytokines. Mesangial cells preferentially induced C/EBP beta after exposure to thapsigargin or tunicamycin; induction of C/EBP delta was modest and transient, and expression of C/EBP alpha was absent. The induction of C/EBP beta correlated with accumulation of C/EBP beta protein and enhanced transcriptional activity of C/EBP. Overexpression of C/EBP beta markedly suppressed TNF-alpha-induced activation of NF-kappa B, independent of its transacting potential. Knockdown of C/EBP beta by small interfering RNA reversed the suppressive effect of ER stress on NF-kappa B. In vivo, preconditioning of mice with ER stress induced renal C/EBP beta and suppressed NF-kappa B-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/EBP beta. These results suggest that ER stress blunts cytokine-triggered activation of NF-kappa B, in part through PERK- and IRE1-mediated preferential induction of C/EBP beta.

• 出版日期2010-1