Endoplasmic reticulum stress-activated C/EBP homologous protein enhances nuclear factor-kappaB signals via repression of peroxisome proliferator-activated receptor gamma.
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Park SH, Choi HJ, Yang H, Do KH, Kim J, Lee DW, Moon Y
Endoplasmic reticulum stress-activated C/EBP homologous protein enhances nuclear factor-kappaB signals via repression of peroxisome proliferator-activated receptor gamma.
J Biol Chem. 2010 Nov 12;285(46):35330-9. doi: 10.1074/jbc.M110.136259. Epub 2010 Sep 9.
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- 20829347 [ View in PubMed]
- Abstract
Endoplasmic reticulum (ER) stress is a causative factor of inflammatory bowel diseases. ER stress mediators, including CCAAT enhancer-binding protein (C/EBP) homologous protein (CHOP), are elevated in intestinal epithelia from patients with inflammatory bowel diseases. The present study arose from the question of how chemical ER stress and CHOP protein were associated with nuclear factor-kappaB (NF-kappaB)-mediated epithelial inflammatory response. In a human intestinal epithelial cell culture model, chemical ER stresses induced proinflammatory cytokine interleukin-8 (IL-8) expression and the nuclear translocation of CHOP protein. CHOP was positively involved in ER-activated IL-8 production and was negatively associated with expression of peroxisome proliferator-activated receptor gamma (PPARgamma). ER stress-induced IL-8 production was enhanced by NF-kappaB activation that was negatively regulated by PPARgamma. Mechanistically, ER stress-induced CHOP suppressed PPARgamma transcription by sequestering C/EBPbeta and limiting availability of C/EBPbeta binding to the PPARgamma promoter. Due to the CHOP-mediated regulation of PPARgamma action, ER stress can enhance proinflammatory NF-kappaB activation and maintain an increased level of IL-8 production in human intestinal epithelial cells. In contrast, PPARgamma was a counteracting regulator of gut inflammatory response through attenuation of NF-kappaB activation. The collective results support the view that balances between CHOP and PPARgamma are crucial for epithelial homeostasis, and disruption of these balances in mucosal ER stress can etiologically affect the progress of human inflammatory bowel diseases.