ER stress depresses NF-kappaB activation in mesangial cells through preferential induction of C/EBP beta.
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-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.
Hayakawa
Kunihiro
K
Department of Molecular Signaling, University of Yamanashi, Shimokato 1110, Chuo, Yamanashi 409-3898, Japan.
Nakajima
Shotaro
S
Hiramatsu
Nobuhiko
N
Okamura
Maro
M
Huang
Tao
T
Saito
Yukinori
Y
Tagawa
Yasuhiro
Y
Tamai
Minori
M
Takahashi
Shuhei
S
Yao
Jian
J
Kitamura
Masanori
M
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D013312:Stress, Physiological / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection; D014415:Tunicamycin / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000378:metabolism
D022782:CCAAT-Enhancer-Binding Protein-beta; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D019284:Thapsigargin; D014415:Tunicamycin; D019892:eIF-2 Kinase; C545014:Cebpb protein, rat; C486557:Ern2 protein, rat