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• W2021617109 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-κB (NF-κB)-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 γ (PPARγ). ER stress-induced IL-8 production was enhanced by NF-κB activation that was negatively regulated by PPARγ. Mechanistically, ER stress-induced CHOP suppressed PPARγ transcription by sequestering C/EBPβ and limiting availability of C/EBPβ binding to the PPARγ promoter. Due to the CHOP-mediated regulation of PPARγ action, ER stress can enhance proinflammatory NF-κB activation and maintain an increased level of IL-8 production in human intestinal epithelial cells. In contrast, PPARγ was a counteracting regulator of gut inflammatory response through attenuation of NF-κB activation. The collective results support the view that balances between CHOP and PPARγ are crucial for epithelial homeostasis, and disruption of these balances in mucosal ER stress can etiologically affect the progress of human inflammatory bowel diseases. 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-κB (NF-κB)-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 γ (PPARγ). ER stress-induced IL-8 production was enhanced by NF-κB activation that was negatively regulated by PPARγ. Mechanistically, ER stress-induced CHOP suppressed PPARγ transcription by sequestering C/EBPβ and limiting availability of C/EBPβ binding to the PPARγ promoter. Due to the CHOP-mediated regulation of PPARγ action, ER stress can enhance proinflammatory NF-κB activation and maintain an increased level of IL-8 production in human intestinal epithelial cells. In contrast, PPARγ was a counteracting regulator of gut inflammatory response through attenuation of NF-κB activation. The collective results support the view that balances between CHOP and PPARγ are crucial for epithelial homeostasis, and disruption of these balances in mucosal ER stress can etiologically affect the progress of human inflammatory bowel diseases. IntroductionEndoplasmic reticulum (ER) 2The abbreviations used are: ERendoplasmic reticulumC/EBPCCAAT enhancer-binding proteinCHOPC/EBP homologous proteindnCHOPdominant negative CHOPIBDinflammatory bowel disease(s)PPARγperoxisome proliferator-activated receptor γTGthapsigarginNF-κBnuclear factor-κBIRE1inositol-requiring ER-to-nucleus signal kinase 1PERKRNA-dependent protein kinase-like ER kinaseATF6activating transcription factor 6. is a protein biosynthesis organelle in which newly synthesized proteins are accurately folded into their proper conformation. However, under diverse pathological stress, folding may occur improperly, or proteins may unfold; the aberrant proteins trigger a severe stress response called the ER stress response (1Kopito R.R. Trends Cell Biol. 2000; 10: 524-530Abstract Full Text Full Text PDF PubMed Scopus (1583) Google Scholar). Phosphorylation of eukaryotic translation initiation factor 2-α (eIF2α) is a highly conserved point of convergence for the distinct signaling pathways that adapt eukaryotic cells to diverse stressful conditions, including ER stress (2Wek R.C. Jiang H.Y. Anthony T.G. Biochem. Soc. Trans. 2006; 34: 7-11Crossref PubMed Scopus (1004) Google Scholar, 3Moenner M. Pluquet O. Bouchecareilh M. Chevet E. Cancer Res. 2007; 67: 10631-10634Crossref PubMed Scopus (338) Google Scholar). It provides stress resistance by global protein translational arrest and induction of numerous stress-triggered genes. CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is a representative stress-responsive factor induced by eIF2α phosphorylation-dependent cellular insults, such as ER stress and nutritional deprivation (4Bruhat A. Jousse C. Wang X.Z. Ron D. Ferrara M. Fafournoux P. J. Biol. Chem. 1997; 272: 17588-17593Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 5Fujii J. Wood K. Matsuda F. Carneiro-Filho B.A. Schlegel K.H. Yutsudo T. Binnington-Boyd B. Lingwood C.A. Obata F. Kim K.S. Yoshida S. Obrig T. Infect. Immun. 2008; 76: 3679-3689Crossref PubMed Scopus (46) Google Scholar, 6Zinszner H. Kuroda M. Wang X. Batchvarova N. Lightfoot R.T. Remotti H. Stevens J.L. Ron D. Genes Dev. 1998; 12: 982-995Crossref PubMed Scopus (1666) Google Scholar). CHOP is a transcription factor that primarily mediates stress-linked apoptosis. Among various pathogenic conditions, ER stress is closely associated with inflammatory diseases in many organs, including intestine, lung, liver, kidney, and central nervous system, and is mediated by proinflammatory triggers, such as microbes, cytokines, and reactive radicals (7Lin W. Harding H.P. Ron D. Popko B. J. Cell Biol. 2005; 169: 603-612Crossref PubMed Scopus (159) Google Scholar, 8Endo M. Mori M. Akira S. Gotoh T. J. Immunol. 2006; 176: 6245-6253Crossref PubMed Scopus (164) Google Scholar, 9Kaser A. Lee A.H. Franke A. Glickman J.N. Zeissig S. Tilg H. Nieuwenhuis E.E. Higgins D.E. Schreiber S. Glimcher L.H. Blumberg R.S. Cell. 2008; 134: 743-756Abstract Full Text Full Text PDF PubMed Scopus (1053) Google Scholar). CHOP is also involved in various inflammatory responses (10Endo M. Oyadomari S. Suga M. Mori M. Gotoh T. J. Biochem. 2005; 138: 501-507Crossref PubMed Scopus (100) Google Scholar, 11Namba T. Tanaka K. Ito Y. Ishihara T. Hoshino T. Gotoh T. Endo M. Sato K. Mizushima T. Am. J. Pathol. 2009; 174: 1786-1798Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 12Suyama K. Ohmuraya M. Hirota M. Ozaki N. Ida S. Endo M. Araki K. Gotoh T. Baba H. Yamamura K. Biochem. Biophys. Res. Commun. 2008; 367: 176-182Crossref PubMed Scopus (39) Google Scholar). Endotoxemia enhances CHOP activation, leading to caspase-processed activation of interleukin-1β (8Endo M. Mori M. Akira S. Gotoh T. J. Immunol. 2006; 176: 6245-6253Crossref PubMed Scopus (164) Google Scholar), and the proinflammatory cytokine tumor necrosis factor-α (TNF-α) induces ER stress and CHOP expression (13Xue X. Piao J.H. Nakajima A. Sakon-Komazawa S. Kojima Y. Mori K. Yagita H. Okumura K. Harding H. Nakano H. J. Biol. Chem. 2005; 280: 33917-33925Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar). In an experimental ulcerative colitis model, mucosal inflammatory response is critically modulated by CHOP protein that mediates production of proinflammatory cytokines and caspase-dependent cytotoxicity (11Namba T. Tanaka K. Ito Y. Ishihara T. Hoshino T. Gotoh T. Endo M. Sato K. Mizushima T. Am. J. Pathol. 2009; 174: 1786-1798Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). ER stress can be a causative factor of inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis. ER stress indicators, including CHOP, are elevated in intestinal epithelia from IBD patients (14Shkoda A. Ruiz P.A. Daniel H. Kim S.C. Rogler G. Sartor R.B. Haller D. Gastroenterology. 2007; 132: 190-207Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 15Burczynski M.E. Peterson R.L. Twine N.C. Zuberek K.A. Brodeur B.J. Casciotti L. Maganti V. Reddy P.S. Strahs A. Immermann F. Spinelli W. Schwertschlag U. Slager A.M. Cotreau M.M. Dorner A.J. J. Mol. Diagn. 2006; 8: 51-61Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar).Gut epithelial tissues are directly confronted with a variety of xenobiotic factors, including intestinal microbiota and dietary components that can trigger host immune responses (16Sansonetti P.J. Curr. Opin. Gastroenterol. 2008; 24: 435-439Crossref PubMed Scopus (34) Google Scholar, 17Cario E. Curr. Opin. Gastroenterol. 2008; 24: 725-732Crossref PubMed Scopus (50) Google Scholar). In response to these triggers, epithelial tissues become tolerant by suppressing excessive mucosal sensitivity to avoid harmful effects of the inflammatory response. Particularly, tolerant mucosal epithelia can be hyporesponsive to commensal bacteria and their components via pattern recognition receptors (18McCole D.F. Barrett K.E. Curr. Opin. Gastroenterol. 2007; 23: 647-654Crossref PubMed Scopus (44) Google Scholar). Mechanistically, pre-exposure to commensals or their components can desensitize human cells to the pattern recognition receptor-linked proinflammatory signals, such as nuclear factor κB (NF-κB) and MAPK signal transduction (19Medvedev A.E. Kopydlowski K.M. Vogel S.N. J. Immunol. 2000; 164: 5564-5574Crossref PubMed Scopus (446) Google Scholar). Epithelial recognition of microbial fingerprints attenuates subsequent triggering of proinflammatory cytokine production. Many gastrointestinal disorders, including IBD, are associated with mucosal intolerance derived from disruption of the epithelial barrier (20Tsianos E.V. Katsanos K. World J. Gastroenterol. 2009; 15: 521-525Crossref PubMed Scopus (31) Google Scholar, 21Srinivasan M. Summerlin D.J. Clin. Immunol. 2009; 133: 411-421Crossref PubMed Scopus (10) Google Scholar, 22Schölmerich J. Ann. N.Y. Acad. Sci. 2006; 1072: 365-378Crossref PubMed Scopus (15) Google Scholar). One critical factor mediating mucosal tolerance is peroxisome proliferator-activated receptor γ (PPARγ). PPARγ is a member of the nuclear receptor superfamily of transcription factors and is a ligand-dependent nuclear receptor. PPARγ is abundantly expressed in adipocytes and colonic epithelium (23Mansén A. Guardiola-Diaz H. Rafter J. Branting C. Gustafsson J.A. Biochem. Biophys. Res. Commun. 1996; 222: 844-851Crossref PubMed Scopus (197) Google Scholar). PPARγ has been investigated as a critical regulator of gut homeostasis because epithelial PPARγ activation generally reduces gene expression of proinflammatory mediators by suppressing NF-κB-linked signals (24Jiang C. Ting A.T. Seed B. Nature. 1998; 391: 82-86Crossref PubMed Scopus (537) Google Scholar, 25Ricote M. Li A.C. Willson T.M. Kelly C.J. Glass C.K. Nature. 1998; 391: 79-82Crossref PubMed Scopus (3241) Google Scholar, 26Su C.G. Wen X. Bailey S.T. Jiang W. Rangwala S.M. Keilbaugh S.A. Flanigan A. Murthy S. Lazar M.A. Wu G.D. J. Clin. Invest. 1999; 104: 383-389Crossref PubMed Scopus (720) Google Scholar). Down-regulation of PPARγ expression may exist within intestinal epithelial cells of IBD patients, which are susceptible to uncontrolled inflammation, and ligands of PPARγ can be efficient in the treatment of IBD (27Kliewer S.A. Sundseth S.S. Jones S.A. Brown P.J. Wisely G.B. Koble C.S. Devchand P. Wahli W. Willson T.M. Lenhard J.M. Lehmann J.M. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 4318-4323Crossref PubMed Scopus (1871) Google Scholar, 28Belluzzi A. Brignola C. Campieri M. Pera A. Boschi S. Miglioli M. N. Engl. J. Med. 1996; 334: 1557-1560Crossref PubMed Scopus (685) Google Scholar). PPARγ expressed in gut epithelium has a protective effect against colonic inflammatory responses to both commensal and pathogenic insults.The present study investigated the nature of chemical ER stress and CHOP protein association with epithelial inflammatory response, including NF-κB-mediated cytokine production in human intestinal epithelial cells. As well, how the mucosal regulatory factor PPARγ is involved in ER stress-mediated cytokine production was assessed.DISCUSSIONThe present study provides molecular insights into ER stress-linked NF-κB activation via regulation of PPARγ by CHOP protein in human enterocytes, which can explain up-regulation of diverse proinflammatory mediators, including cytokines, eicosanoids, and adhesion molecules in response to ER stress. Another recent study also suggested that CHOP can affect interleukin-1β activation, which is only limited to caspase-processed cytokines (8Endo M. Mori M. Akira S. Gotoh T. J. Immunol. 2006; 176: 6245-6253Crossref PubMed Scopus (164) Google Scholar, 12Suyama K. Ohmuraya M. Hirota M. Ozaki N. Ida S. Endo M. Araki K. Gotoh T. Baba H. Yamamura K. Biochem. Biophys. Res. Commun. 2008; 367: 176-182Crossref PubMed Scopus (39) Google Scholar). Other than CHOP-linked modulation, ER stress sensor molecules, such as inositol-requiring ER-to-nucleus signal kinase 1 (IRE1), RNA-dependent protein kinase-like ER kinase (PERK), and activating transcription factor 6 (ATF6), can trigger the NF-κB signaling pathway to induce proinflammatory mediators (40Hung J.H. Su I.J. Lei H.Y. Wang H.C. Lin W.C. Chang W.T. Huang W. Chang W.C. Chang Y.S. Chen C.C. Lai M.D. J. Biol. Chem. 2004; 279: 46384-46392Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). IRE1 interacts with the C terminus of TNF receptor-associated factor 2, which involves ER stress-induced NF-κB activation (41Kaneko M. Niinuma Y. Nomura Y. Biol. Pharm. Bull. 2003; 26: 931-935Crossref PubMed Scopus (208) Google Scholar). PERK activates NF-κB via phosphorylation of eIF2α, inhibiting translation. Phosphorylation of eIF2α also triggers activation of NF-κB by eukaryotic initiation factor 2 α kinase 4, another kinase of eIF2α (39Jiang H.Y. Wek S.A. McGrath B.C. Scheuner D. Kaufman R.J. Cavener D.R. Wek R.C. Mol. Cell Biol. 2003; 23: 5651-5663Crossref PubMed Scopus (350) Google Scholar). ATF6 also activates NF-κB signals via the protein kinase B signaling pathway. ER stress has been positively associated with chronic proinflammatory diseases (7Lin W. Harding H.P. Ron D. Popko B. J. Cell Biol. 2005; 169: 603-612Crossref PubMed Scopus (159) Google Scholar, 42Kahle P.J. Haass C. EMBO Rep. 2004; 5: 681-685Crossref PubMed Scopus (110) Google Scholar, 43Araki E. Oyadomari S. Mori M. Intern. Med. 2003; 42: 7-14Crossref PubMed Scopus (136) Google Scholar). Particularly in intestinal epithelia, ER stress-induced X-box binding protein 1 confers genetic susceptibility to human IBD, including ulcerative colitis and Crohn's disease (9Kaser A. Lee A.H. Franke A. Glickman J.N. Zeissig S. Tilg H. Nieuwenhuis E.E. Higgins D.E. Schreiber S. Glimcher L.H. Blumberg R.S. Cell. 2008; 134: 743-756Abstract Full Text Full Text PDF PubMed Scopus (1053) Google Scholar).Because NF-κB activation occurs earlier than CHOP induction by ER stress, the CHOP-mediated proinflammatory response may be crucial in maintaining the whole inflammatory process. Early activation of NF-κB signals may be associated with other ER stress sensor molecules, such as IRE1, PERK, and ATF6. Instead, CHOP was presently associated with maintenance of low levels of PPARγ in human epithelia. Without CHOP action in the epithelial cells, PPARγ was strongly up-regulated, which abolished proinflammatory cytokine production by ER stress. Therefore, CHOP is expected to be a crucial mediator to support prolonged inflammatory responses to mucosal insults by ER stress. In addition, CHOP was also partly involved in ER stress-induced cell death (supplemental Fig. S2, A and B). Chemical ER stress inducers, including TG and tunicamycin, at higher doses than those in proinflammatory responses caused epithelial cell death, which was also associated with CHOP protein. Particularly, ER stress has been associated with diverse chronic inflammatory disease rather than acute inflammatory responses (11Namba T. Tanaka K. Ito Y. Ishihara T. Hoshino T. Gotoh T. Endo M. Sato K. Mizushima T. Am. J. Pathol. 2009; 174: 1786-1798Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 44Jorgensen E. Stinson A. Shan L. Yang J. Gietl D. Albino A.P. BMC Cancer. 2008; 8: 229Crossref PubMed Scopus (147) Google Scholar, 45Koumenis C. Curr. Mol. Med. 2006; 6: 55-69Crossref PubMed Scopus (196) Google Scholar). Additional proinflammatory signals can exist to support persistent NF-κB signals in response to ER stress. One example is boosting kinases, including small GTPase p21-activated kinase, for prolonged phosphorylation of NF-κB (46Orr A.W. Hahn C. Blackman B.R. Schwartz M.A. Circ. Res. 2008; 103: 671-679Crossref PubMed Scopus (74) Google Scholar). In contrast, the results of the present study support the suggestion that CHOP controls cellular levels of PPAR-suppressing NF-κB signals, finally achieving a high level of proinflammatory cytokine production.Intestinal epithelial NF-κB can contribute to up-regulation of proinflammatory cytokines related to chronic intestinal inflammatory diseases, such as IBD. In response to the proinflammatory stress, PPARγ is a critical regulator of gut homeostasis by suppressing NF-κB-linked signals as shown both previously (24Jiang C. Ting A.T. Seed B. Nature. 1998; 391: 82-86Crossref PubMed Scopus (537) Google Scholar, 25Ricote M. Li A.C. Willson T.M. Kelly C.J. Glass C.K. Nature. 1998; 391: 79-82Crossref PubMed Scopus (3241) Google Scholar, 26Su C.G. Wen X. Bailey S.T. Jiang W. Rangwala S.M. Keilbaugh S.A. Flanigan A. Murthy S. Lazar M.A. Wu G.D. J. Clin. Invest. 1999; 104: 383-389Crossref PubMed Scopus (720) Google Scholar) and presently. Impaired expression of PPARγ without any mutation of PPARγ sequences in patients with ulcerative colitis indicates that PPARγ is a key mediator of anti-inflammatory responses in human gut epithelia and can be a crucial target of therapeutic agents of IBD (47Dubuquoy L. Jansson E.A. Deeb S. Rakotobe S. Karoui M. Colombel J.F. Auwerx J. Pettersson S. Desreumaux P. Gastroenterology. 2003; 124: 1265-1276Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar). The human gut is continuously confronted by commensal bacteria, and human intestinal epithelial cells are generally the first contact targets of the bacteria. Gut epithelial cells show hyporesponsiveness to bacterial pattern moiety, particularly attenuation of proinflammatory NF-κB signals by PPARγ. Mechanistically, commensal-mediated PPARγ attenuates epithelial inflammatory responses by triggering nuclear export of p65 protein in complex with PPARγ (48Kelly D. Campbell J.I. King T.P. Grant G. Jansson E.A. Coutts A.G. Pettersson S. Conway S. Nat. Immunol. 2004; 5: 104-112Crossref PubMed Scopus (841) Google Scholar). Moreover, PPARγ also can affect proinflammatory cytokine production via an indirect activation of NF-κB. PPARγ interferes with the cytosol-to-membrane translocation of protein kinase Cα, which induces cellular desensitization to proinflammatory stimulation (49von Knethen A. Soller M. Tzieply N. Weigert A. Johann A.M. Jennewein C. Köhl R. Brüne B. J. Cell Biol. 2007; 176: 681-694Crossref PubMed Scopus (71) Google Scholar). Whereas C/EBPβ can suppress NF-κB activation by enhancing PPARγ production in the present study, another explanation can be that C/EBPβ interferes with NF-κB signals by directly snatching p65 protein (50Zwergal A. Quirling M. Saugel B. Huth K.C. Sydlik C. Poli V. Neumeier D. Ziegler-Heitbrock H.W. Brand K. J. Immunol. 2006; 177: 665-672Crossref PubMed Scopus (50) Google Scholar). Moreover, bacterial lipopolysaccharide delays the activation of PPARγ, which attenuates proinflammatory responses by oxidative stress or mucosal ribotoxic stresses in human epithelial cells (51Moon Y. Yang H. Park S.H. Toxicol. Appl. Pharmacol. 2008; 231: 94-102Crossref PubMed Scopus (28) Google Scholar, 52Von Knethen A.A. Brüne B. FASEB J. 2001; 15: 535-544Crossref PubMed Scopus (69) Google Scholar). However, although activation of intestinal epithelial NF-κB increases harmful proinflammatory cytokines related to chronic intestinal inflammatory diseases or colon cancers, it is not always bad news in terms of the defense against microbial infection. In diverse mechanical injury models, NF-κB is involved in protective action, including wound healing responses, in particular by promoting cellular proliferation (53Ishida Y. Kondo T. Kimura A. Matsushima K. Mukaida N. J. Immunol. 2006; 176: 5598-5606Crossref PubMed Scopus (134) Google Scholar, 54Egan L.J. de Lecea A. Lehrman E.D. Myhre G.M. Eckmann L. Kagnoff M.F. Am. J. Physiol. Cell Physiol. 2003; 285: C1028-C1035Crossref PubMed Scopus (76) Google Scholar). Moreover, NF-κB promotes the reconstitution of injured epithelial monolayer via NF-κB target genes, such as inducible nitric-oxide synthase and cyclooxygenase-2, which are strong mediators of epithelial migration to the injury site (55Noiri E. Peresleni T. Srivastava N. Weber P. Bahou W.F. Peunova N. Goligorsky M.S. Am. J. Physiol. 1996; 270: C794-C802Crossref PubMed Google Scholar, 56Cowan M.J. Coll T. Shelhamer J.H. J. Appl. Physiol. 2006; 101: 1127-1135Crossref PubMed Scopus (11) Google Scholar). Thus, it can be speculated that ER stress-activated NF-κB can protect intestinal epithelial cells from the toxic insults of proinflammatory response and even facilitates the wound healing process after epithelial injury to lessen microbial translocation (57Fukata M. Michelsen K.S. Eri R. Thomas L.S. Hu B. Lukasek K. Nast C.C. Lechago J. Xu R. Naiki Y. Soliman A. Arditi M. Abreu M.T. Am. J. Physiol. Gastrointest. Liver Physiol. 2005; 288: G1055-G1065Crossref PubMed Scopus (418) Google Scholar). Therefore, more careful observations are needed for homeostatic counteraction between activated NF-κB and PPARγ-mediated regulation in the intestinal epithelia. In particular, the present study provides a promising insight into the molecular mechanism of epithelial decision in the progress of ER stress-linked IBD. IntroductionEndoplasmic reticulum (ER) 2The abbreviations used are: ERendoplasmic reticulumC/EBPCCAAT enhancer-binding proteinCHOPC/EBP homologous proteindnCHOPdominant negative CHOPIBDinflammatory bowel disease(s)PPARγperoxisome proliferator-activated receptor γTGthapsigarginNF-κBnuclear factor-κBIRE1inositol-requiring ER-to-nucleus signal kinase 1PERKRNA-dependent protein kinase-like ER kinaseATF6activating transcription factor 6. is a protein biosynthesis organelle in which newly synthesized proteins are accurately folded into their proper conformation. However, under diverse pathological stress, folding may occur improperly, or proteins may unfold; the aberrant proteins trigger a severe stress response called the ER stress response (1Kopito R.R. Trends Cell Biol. 2000; 10: 524-530Abstract Full Text Full Text PDF PubMed Scopus (1583) Google Scholar). Phosphorylation of eukaryotic translation initiation factor 2-α (eIF2α) is a highly conserved point of convergence for the distinct signaling pathways that adapt eukaryotic cells to diverse stressful conditions, including ER stress (2Wek R.C. Jiang H.Y. Anthony T.G. Biochem. Soc. Trans. 2006; 34: 7-11Crossref PubMed Scopus (1004) Google Scholar, 3Moenner M. Pluquet O. Bouchecareilh M. Chevet E. Cancer Res. 2007; 67: 10631-10634Crossref PubMed Scopus (338) Google Scholar). It provides stress resistance by global protein translational arrest and induction of numerous stress-triggered genes. CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) is a representative stress-responsive factor induced by eIF2α phosphorylation-dependent cellular insults, such as ER stress and nutritional deprivation (4Bruhat A. Jousse C. Wang X.Z. Ron D. Ferrara M. Fafournoux P. J. Biol. Chem. 1997; 272: 17588-17593Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 5Fujii J. Wood K. Matsuda F. Carneiro-Filho B.A. Schlegel K.H. Yutsudo T. Binnington-Boyd B. Lingwood C.A. Obata F. Kim K.S. Yoshida S. Obrig T. Infect. Immun. 2008; 76: 3679-3689Crossref PubMed Scopus (46) Google Scholar, 6Zinszner H. Kuroda M. Wang X. Batchvarova N. Lightfoot R.T. Remotti H. Stevens J.L. Ron D. Genes Dev. 1998; 12: 982-995Crossref PubMed Scopus (1666) Google Scholar). CHOP is a transcription factor that primarily mediates stress-linked apoptosis. Among various pathogenic conditions, ER stress is closely associated with inflammatory diseases in many organs, including intestine, lung, liver, kidney, and central nervous system, and is mediated by proinflammatory triggers, such as microbes, cytokines, and reactive radicals (7Lin W. Harding H.P. Ron D. Popko B. J. Cell Biol. 2005; 169: 603-612Crossref PubMed Scopus (159) Google Scholar, 8Endo M. Mori M. Akira S. Gotoh T. J. Immunol. 2006; 176: 6245-6253Crossref PubMed Scopus (164) Google Scholar, 9Kaser A. Lee A.H. Franke A. Glickman J.N. Zeissig S. Tilg H. Nieuwenhuis E.E. Higgins D.E. Schreiber S. Glimcher L.H. Blumberg R.S. Cell. 2008; 134: 743-756Abstract Full Text Full Text PDF PubMed Scopus (1053) Google Scholar). CHOP is also involved in various inflammatory responses (10Endo M. Oyadomari S. Suga M. Mori M. Gotoh T. J. Biochem. 2005; 138: 501-507Crossref PubMed Scopus (100) Google Scholar, 11Namba T. Tanaka K. Ito Y. Ishihara T. Hoshino T. Gotoh T. Endo M. Sato K. Mizushima T. Am. J. Pathol. 2009; 174: 1786-1798Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 12Suyama K. Ohmuraya M. Hirota M. Ozaki N. Ida S. Endo M. Araki K. Gotoh T. Baba H. Yamamura K. Biochem. Biophys. Res. Commun. 2008; 367: 176-182Crossref PubMed Scopus (39) Google Scholar). Endotoxemia enhances CHOP activation, leading to caspase-processed activation of interleukin-1β (8Endo M. Mori M. Akira S. Gotoh T. J. Immunol. 2006; 176: 6245-6253Crossref PubMed Scopus (164) Google Scholar), and the proinflammatory cytokine tumor necrosis factor-α (TNF-α) induces ER stress and CHOP expression (13Xue X. Piao J.H. Nakajima A. Sakon-Komazawa S. Kojima Y. Mori K. Yagita H. Okumura K. Harding H. Nakano H. J. Biol. Chem. 2005; 280: 33917-33925Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar). In an experimental ulcerative colitis model, mucosal inflammatory response is critically modulated by CHOP protein that mediates production of proinflammatory cytokines and caspase-dependent cytotoxicity (11Namba T. Tanaka K. Ito Y. Ishihara T. Hoshino T. Gotoh T. Endo M. Sato K. Mizushima T. Am. J. Pathol. 2009; 174: 1786-1798Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). ER stress can be a causative factor of inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis. ER stress indicators, including CHOP, are elevated in intestinal epithelia from IBD patients (14Shkoda A. Ruiz P.A. Daniel H. Kim S.C. Rogler G. Sartor R.B. Haller D. Gastroenterology. 2007; 132: 190-207Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, 15Burczynski M.E. Peterson R.L. Twine N.C. Zuberek K.A. Brodeur B.J. Casciotti L. Maganti V. Reddy P.S. Strahs A. Immermann F. Spinelli W. Schwertschlag U. Slager A.M. Cotreau M.M. Dorner A.J. J. Mol. Diagn. 2006; 8: 51-61Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar).Gut epithelial tissues are directly confronted with a variety of xenobiotic factors, including intestinal microbiota and dietary components that can trigger host immune responses (16Sansonetti P.J. Curr. Opin. Gastroenterol. 2008; 24: 435-439Crossref PubMed Scopus (34) Google Scholar, 17Cario E. Curr. Opin. Gastroenterol. 2008; 24: 725-732Crossref PubMed Scopus (50) Google Scholar). In response to these triggers, epithelial tissues become tolerant by suppressing excessive mucosal sensitivity to avoid harmful effects of the inflammatory response. Particularly, tolerant mucosal epithelia can be hyporesponsive to commensal bacteria and their components via pattern recognition receptors (18McCole D.F. Barrett K.E. Curr. Opin. Gastroenterol. 2007; 23: 647-654Crossref PubMed Scopus (44) Google Scholar). Mechanistically, pre-exposure to commensals or their components can desensitize human cells to the pattern recognition receptor-linked proinflammatory signals, such as nuclear factor κB (NF-κB) and MAPK signal transduction (19Medvedev A.E. Kopydlowski K.M. Vogel S.N. J. Immunol. 2000; 164: 5564-5574Crossref PubMed Scopus (446) Google Scholar). Epithelial recognition of microbial fingerprints attenuates subsequent triggering of proinflammatory cytokine production. Many gastrointestinal disorders, including IBD, are associated with mucosal intolerance derived from disruption of the epithelial barrier (20Tsianos E.V. Katsanos K. World J. Gastroenterol. 2009; 15: 521-525Crossref PubMed Scopus (31) Google Scholar, 21Srinivasan M. Summerlin D.J. Clin. Immunol. 2009; 133: 411-421Crossref PubMed Scopus (10) Google Scholar, 22Schölmerich J. Ann. N.Y. Acad. Sci. 2006; 1072: 365-378Crossref PubMed Scopus (15) Google Scholar). One critical factor mediating mucosal tolerance is peroxisome proliferator-activated receptor γ (PPARγ). PPARγ is a member of the nuclear receptor superfamily of transcription factors and is a ligand-dependent nuclear receptor. PPARγ is abundantly expressed in adipocytes and colonic epithelium (23Mansén A. Guardiola-Diaz H. Rafter J. Branting C. Gustafsson J.A. Biochem. Biophys. Res. Commun. 1996; 222: 844-851Crossref PubMed Scopus (197) Google Scholar). PPARγ has been investigated as a critical regulator of gut homeostasis because epithelial PPARγ activation generally reduces gene expression of proinflammatory mediators by suppressing NF-κB-linked signals (24Jiang C. Ting A.T. Seed B. Nature. 1998; 391: 82-86Crossref PubMed Scopus (537) Google Scholar, 25Ricote M. Li A.C. Willson T.M. Kelly C.J. Glass C.K. Nature. 1998; 391: 79-82Crossref PubMed Scopus (3241) Google Scholar, 26Su C.G. Wen X. Bailey S.T. Jiang W. Rangwala S.M. Keilbaugh S.A. Flanigan A. Murthy S. Lazar M.A. Wu G.D. J. Clin. Invest. 1999; 104: 383-389Crossref PubMed Scopus (720) Google Scholar). Down-regulation of PPARγ expression may exist within intestinal epithelial cells of IBD patients, which are susceptible to uncontrolled inflammation, and ligands of PPARγ can be efficient in the treatment of IBD (27Kliewer S.A. Sundseth S.S. Jones S.A. Brown P.J. Wisely G.B. Koble C.S. Devchand P. Wahli W. Willson T.M. Lenhard J.M. Lehmann J.M. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 4318-4323Crossref PubMed Scopus (1871) Google Scholar, 28Belluzzi A. Brignola C. Campieri M. Pera A. Boschi S. Miglioli M. N. Engl. J. Med. 1996; 334: 1557-1560Crossref PubMed Scopus (685) Google Scholar). PPARγ expressed in gut epithelium has a protective effect against colonic inflammatory responses to both commensal and pathogenic insults.The present study investigated the nature of chemical ER stress and CHOP protein association with epithelial inflammatory response, including NF-κB-mediated cytokine production in human intestinal epithelial cells. As well, how the mucosal regulatory factor PPARγ is involved in ER stress-mediated cytokine production was assessed." @default.
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