Repression of peroxisome proliferator-activated receptor gamma by mucosal ribotoxic insult-activated CCAAT/enhancer-binding protein homologous protein.
CCAAT/enhancer-binding protein homologous protein (CHOP) is a crucial stress-responsive factor in various mucosal injuries, including cellular translational stress conditions. In this study, chemical ribosome-inactivating stresses were assessed for their effects on stress-inducible CHOP expression and its association with epithelial inflammatory cytokine production. Several representative ribotoxic agents (deoxynivalenol, anisomycin, and 15-acetyldeoxynivalenol) enhanced CHOP expression and its nuclear translocation in human intestinal epithelial cells. Moreover, CHOP was a strong positive regulator of IL-8 production, but CHOP-mediated IL-8 production was inversely associated with expression of the mucosal regulatory factor peroxisome proliferator-activated receptor γ (PPARγ). Based on our recent report that PPARγ is a negative regulator of mRNA stability of IL-8, PPARγ was linked to a notable mRNA stabilizing protein, HuR, since ribotoxin-induced IL-8 mRNA is stabilized by HuR protein. Expression of exogenous PPARγ suppressed ribotoxin-triggered cytoplasmic translocation of HuR. In contrast, PPARγ-regulating CHOP was a positive modulator of HuR protein export from nuclei. Taken together, the results indicate that ribotoxin-induced CHOP protein is positively associated with production of proinflammatory cytokine IL-8, but it downregulates PPARγ action, subsequently allowing the cytosolic translocation of HuR protein and stabilization of IL-8 mRNA in gut epithelial cells. CHOP and PPARγ may represent critical mechanistic links between ribotoxic stress and proinflammatory cytokine production, and they may have a broader functional significance with regard to gastrointestinal stresses by toxic mucosal insults.
Park
Seong-Hwan
SH
Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan, Korea.
Choi
Hye Jin
HJ
Yang
Hyun
H
Do
Kee Hun
KH
Kim
Juil
J
Moon
Yuseok
Y
D000841:Anisomycin / Q000633:toxicity; D000954:Antigens, Surface / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D018928:Immunity, Mucosal / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000096:biosynthesis / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism; D018613:Microscopy, Confocal; D047495:PPAR gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000633:toxicity; D016601:RNA-Binding Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051742:Transcription Factor CHOP / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D014162:Transfection; D014255:Trichothecenes / Q000633:toxicity
D000954:Antigens, Surface; C497249:DDIT3 protein, human; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D016209:Interleukin-8; D047495:PPAR gamma; D011500:Protein Synthesis Inhibitors; D016601:RNA-Binding Proteins; D014255:Trichothecenes; D051742:Transcription Factor CHOP; D000841:Anisomycin; C046760:15-acetyldeoxynivalenol; C007262:deoxynivalenol