Endoplasmic Reticulum Stress-activated C/EBP Homologous Protein Enhances Nuclear Factor-κB Signals via Repression of Peroxisome Proliferator-activated Receptor γ

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-kappa B (NF-kappa B)-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 (PPAR gamma). ER stress-induced IL-8 production was enhanced by NF-kappa B activation that was negatively regulated by PPAR gamma. Mechanistically, ER stress-induced CHOP suppressed PPAR gamma transcription by sequestering C/EBP beta and limiting availability of C/EBP beta binding to the PPAR gamma promoter. Due to the CHOP-mediated regulation of PPAR gamma action, ER stress can enhance proinflammatory NF-kappa B activation and maintain an increased level of IL-8 production in human intestinal epithelial cells. In contrast, PPAR gamma was a counteracting regulator of gut inflammatory response through attenuation of NF-kappa B activation. The collective results support the view that balances between CHOP and PPAR gamma are crucial for epithelial homeostasis, and disruption of these balances in mucosal ER stress can etiologically affect the progress of human inflammatory bowel diseases.