ER Stress Depresses NF-κB Activation in Mesangial Cells through Preferential Induction of C/EBPβ

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