title: Endoplasmic reticulum stress-induced IRE1α activation mediates cross-talk of GSK-3β and XBP-1 to regulate inflammatory cytokine production.
abstract: IL-1β and TNF-α are important proinflammatory cytokines that respond to mutated self-antigens of tissue damage and exogenous pathogens. The endoplasmic reticulum (ER) stress and unfolded protein responses are related to the induction of proinflammatory cytokines. However, the detailed molecular pathways by which ER stress mediates cytokine gene expression have not been investigated. In this study, we found that ER stress-induced inositol-requiring enzyme (IRE)1α activation differentially regulates proinflammatory cytokine gene expression via activation of glycogen synthase kinase (GSK)-3β and X-box binding protein (XBP)-1. Surprisingly, IL-1β gene expression was modulated by IRE1α-mediated GSK-3β activation, but not by XBP-1. However, IRE1α-mediated XBP-1 splicing regulated TNF-α gene expression. SB216763, a GSK-3 inhibitor, selectively inhibited IL-1β gene expression, whereas the IRE1α RNase inhibitor STF083010 suppressed only TNF-α production. Additionally, inhibition of GSK-3β greatly increased IRE1α-dependent XBP-1 splicing. Our results identify an unsuspected differential role of downstream mediators GSK-3β and XBP-1 in ER stress-induced IRE1α activation that regulates cytokine production through signaling cross-talk. These results have important implications in the regulation of inflammatory pathways during ER stress, and they suggest novel therapeutic targets for diseases in which meta-inflammation plays a key role.
authors.affiliation: School of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea;
authors.forename: Sena
authors.initials: S
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea;
authors.forename: Yeonsoo
authors.initials: Y
authors.lastname: Joe
authors.affiliation: School of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea;
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, Graduate School, Ajou University, Suwon 443-721, Korea; Department of Biomedical Sciences, Graduate School, Ajou University, Suwon 443-721, Korea;
authors.forename: You-Sun
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Pain Medicine, Wonkwang University School of Medicine, Iksan 570-749, Korea;
authors.forename: Sun Oh
authors.initials: SO
authors.lastname: Jeong
authors.affiliation: Department of Anesthesiology and Pain Medicine, Wonkwang University School of Medicine, Iksan 570-749, Korea;
authors.forename: Hyun-Ock
authors.initials: HO
authors.lastname: Pae
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY 10065; and.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Korea.
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
authors.affiliation: School of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea; chung@ulsan.ac.kr.
authors.forename: Hun Taeg
authors.initials: HT
authors.lastname: Chung
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012326:RNA Splicing; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D000071701:Regulatory Factor X Transcription Factors; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C510185:Ern1 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D004722:Endoribonucleases
references.citation: Genes Dev. 1999 May 15;13(10):1211-33
references.pmid: 10346810
references.citation: J Biol Chem. 2004 Jun 18;279(25):25935-8
references.pmid: 15070890
references.citation: Annu Rev Biochem. 2005;74:739-89
references.pmid: 15952902
references.citation: Innate Immun. 2014 Nov;20(8):799-815
references.pmid: 24217221
references.citation: J Am Soc Nephrol. 2010 Feb;21(2):284-94
references.pmid: 20093356
references.citation: J Exp Med. 2009 Sep 28;206(10):2151-9
references.pmid: 19752183
references.citation: Arterioscler Thromb Vasc Biol. 2012 Jan;32(1):82-91
references.pmid: 21998135
references.citation: FASEB J. 2014 Feb;28(2):978-97
references.pmid: 24165480
references.citation: Antioxid Redox Signal. 2009 Sep;11(9):2353-64
references.pmid: 19187000
references.citation: Nature. 1999 Jan 21;397(6716):271-4
references.pmid: 9930704
references.citation: J Clin Invest. 2005 May;115(5):1111-9
references.pmid: 15864338
references.citation: Mol Cell Biol. 2004 Feb;24(3):1365-77
references.pmid: 14729979
references.citation: Nature. 2007 Oct 18;449(7164):819-26
references.pmid: 17943118
references.citation: Trends Mol Med. 2012 Jan;18(1):59-68
references.pmid: 21889406
references.citation: Am J Physiol Gastrointest Liver Physiol. 2002 Jul;283(1):G204-11
references.pmid: 12065308
references.citation: Mol Cell Biol. 2006 Apr;26(8):3071-84
references.pmid: 16581782
references.citation: Biochem Biophys Res Commun. 2011 Jan 7;404(1):1-5
references.pmid: 21094129
references.citation: Neurochem Res. 2007 Apr-May;32(4-5):577-95
references.pmid: 16944320
references.citation: Int Immunopharmacol. 2007 Oct;7(10):1271-85
references.pmid: 17673142
references.citation: J Pharmacol Exp Ther. 2009 May;329(2):524-31
references.pmid: 19188482
references.citation: Biol Pharm Bull. 2003 Jul;26(7):931-5
references.pmid: 12843613
references.citation: Int J Inflam. 2011;2011:259462
references.pmid: 21755026
references.citation: J Cell Biol. 2012 Jun 25;197(7):857-67
references.pmid: 22733998
references.citation: Am J Physiol Cell Physiol. 2007 Jul;293(1):C411-8
references.pmid: 17475668
references.citation: Circ Res. 2012 Jan 6;110(1):174-89
references.pmid: 22223213
references.citation: Can J Physiol Pharmacol. 2006 Jan;84(1):39-48
references.pmid: 16845889
references.citation: Nat Immunol. 2010 May;11(5):411-8
references.pmid: 20351694
references.citation: J Biol Chem. 2003 Oct 10;278(41):39583-90
references.pmid: 12871932
references.citation: J Inflamm (Lond). 2012 Jun 12;9(1):23
references.pmid: 22691598
references.citation: J Cell Sci. 2005 Jan 1;118(Pt 1):89-99
references.pmid: 15585578
references.citation: Int J Cell Biol. 2012;2012:930710
references.pmid: 22675363
references.citation: Mol Biol Cell. 1999 Nov;10(11):3787-99
references.pmid: 10564271
references.citation: Nat Immunol. 2005 Aug;6(8):777-84
references.pmid: 16007092