Expression of human REG family genes in inflammatory bowel disease and their molecular mechanism
- 61 Downloads
Abstract
The pathophysiology of inflammatory bowel disease (IBD) reflects a balance between mucosal injury and reparative mechanisms. Some regenerating gene (Reg) family members have been reported to be expressed in Crohn’s disease (CD) and ulcerative colitis (UC) and to be involved as proliferative mucosal factors in IBD. However, expression of all the REG family genes in IBD is still unclear. Here, we analyzed expression of all the REG family genes (REG Iα, REG Iβ, REG III, HIP/PAP, and REG IV) in biopsy specimens of UC and CD by real-time RT-PCR. REG Iα, REG Iβ, and REG IV genes were overexpressed in CD samples. REG IV gene was also overexpressed in UC samples. We further analyzed the expression mechanisms of REG Iα, REG Iβ, and REG IV genes in LS-174T and HT-29 human colonic epithelial cells. The expression of REG Iα was significantly induced by IL-6 or IL-22, and REG Iβ was induced by IL-22. Deletion analyses revealed that three regions (− 220~− 211, − 179~− 156, and − 146~− 130) in REG Iα and the region (− 274~− 260) in REG Iβ promoter were responsible for the activation by IL-22/IL-6. The promoters contain consensus transcription factor binding sequences for MZF1, RTEF1/TEAD4, and STAT3 in REG Iα, and HLTF/FOXN2F in REG Iβ, respectively. The introduction of siRNA for MZF1, RTEF1/TEAD4, STAT3, and HLTF/FOXN2F abolished the transcription of REG Iα and REG Iβ. The gene activation mechanisms of REG Iα/REG Iβ may play a role in colon mucosal regeneration in IBD.
Keywords
Crohn’s disease (CD) Ulcerative colitis (UC) REG family genes TranscriptionNotes
Compliance with ethical standards
This work was performed with approval of the Review Board(s) of Saiseikai Nara Hospital and Nara Medical University Hospital.
Conflicts of Interest
The authors declare that they have no conflict of interest.
References
- 1.Takasawa S. Regenerating gene (REG) product and its potential clinical usage. Expert Opin Ther Targets. 2016;20:541–50.CrossRefGoogle Scholar
- 2.Terazono K, Yamamoto H, Takasawa S, et al. A novel gene activated in regenerating islets. J Biol Chem. 1988;263:2111–4.PubMedGoogle Scholar
- 3.Watanabe T, Yonemura Y, Yonekura H, Suzuki Y, Miyashita H, Sugiyama K, et al. Pancreatic beta-cell replication and amelioration of surgical diabetes by Reg protein. Proc Natl Acad Sci U S A. 1994;91:3589–92.CrossRefGoogle Scholar
- 4.Yonemura Y, Sakurai S, Yamamoto H, Endou Y, Kawamura T, Bandou E, et al. REG gene expression is associated with the infiltrating growth of gastric carcinoma. Cancer. 2003;98:1394–400.CrossRefGoogle Scholar
- 5.Yamauchi A, Takahashi I, Takasawa S, Nata K, Noguchi N, Ikeda T, et al. Thiazolidinediones inhibit REG Iα gene transcription in gastrointestinal cancer cells. Biochem Biophys Res Commun. 2009;379:743–8.CrossRefGoogle Scholar
- 6.Lawrance IC, Fiocchi C, Chakravarti S. Ulcerative colitis and Crohn’s disease: distinctive gene expression profiles and novel susceptibility candidate genes. Hum Mol Genet. 2001;10:445–56.CrossRefGoogle Scholar
- 7.Ogawa H, Fukushima K, Naito H, Funayama Y, Unno M, Takahashi KI, et al. Increased expression of HIP/PAP and regenerating gene III in human inflammatory bowel disease and a murine bacterial reconstitution model. Inflamm Bowel Dis. 2003;9:162–70.CrossRefGoogle Scholar
- 8.Granlund AVB, Beisvag V, Torp SH, et al. Activation of REG family proteins in colitis. Scand J Gastroenterol. 2011;46:1316–23.CrossRefGoogle Scholar
- 9.Yoshimoto K, Fujimoto T, Itaya-Hironaka A, Miyaoka T, Sakuramoto-Tsuchida S, Yamauchi A, et al. Involvement of autoimmunity to REG, a regeneration factor, in patients with primary Sjögren’s syndrome. Clin Exp Immunol. 2013;174:1–9.CrossRefGoogle Scholar
- 10.Tsuchida C, Sakuramoto-Tsuchida S, Takeda M, et al. Expression of REG family genes in human inflammatory bowel diseases and its regulation. Biochem Biophys Rep. 2017;12:198–205.PubMedPubMedCentralGoogle Scholar
- 11.Fujimura T, Fujimoto T, Itaya-Hironaka A, et al. Interleukin-6/STAT pathway is responsible for the induction of gene expression of REG Iα, a new auto-antigen in Sjögren’s syndrome patients, in salivary duct epithelial cells. Biochem Biophys Rep. 2015;2:69–74.PubMedPubMedCentralGoogle Scholar
- 12.Shobatake R, Takasawa K, Ota H, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, et al. Up-regulation of POMC and CART mRNAs by intermittent hypoxia via GATA transcription factors in human neuronal cells. Int J Biochem Cell Biol. 2018;95:100–7.CrossRefGoogle Scholar
- 13.Yamauchi A, Itaya-Hironaka A, Sakuramoto-Tsuchida S, et al. Synergistic activations of REG Iα and REG Iβ promoters by IL-6 and glucocorticoids through JAK/STAT pathway in human pancreatic β cells. J Diabetes Res. 2015;173058:2015.Google Scholar
- 14.Tsujinaka H, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Shobatake R, Makino M, et al. Statins decrease vascular epithelial growth factor expression via down-regulation of receptor for advanced glycation end-products. Heliyon. 2017;3:e00401.CrossRefGoogle Scholar
- 15.Uchiyama T, Ota H, Itaya-Hironaka A, et al. Up-regulation of selenoprotein P and HIP/PAP mRNAs in hepatocytes by intermittent hypoxia via down-regulation of miR-203. Biochem Biophys Rep. 2017;11:130–7.PubMedPubMedCentralGoogle Scholar
- 16.Dieckgraefe BK, Crimmins DL, Landt V, Houchen C, Anant S, Porche-Sorbet R, et al. Expression of the regenerating gene family in inflammatory bowel disease mucosa: Reg Iα upregulation, processing, and antiapoptotic activity. J Investig Med. 2002;50:421–34.CrossRefGoogle Scholar
- 17.Takasawa S, Ikeda T, Akiyama T, Nata K, Nakagawa K, Shervani NJ, et al. Cyclin D1 activation through ATF-2 in Reg-induced pancreatic β-cell regeneration. FEBS Lett. 2006;580:585–91.CrossRefGoogle Scholar
- 18.Planas R, Alba A, Carrillo J, Puertas MC, Ampudia R, Pastor X, et al. Reg (regenerating) gene overexpression in islets from non-obese diabetic mice with accelerated diabetes: role of IFNβ. Diabetologia. 2006;49:2379–87.CrossRefGoogle Scholar
- 19.Fukui H, Kinoshita Y, Maekawa T, Okada A, Waki S, Hassan MS, et al. Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats. Gastroenterology. 1998;115:1483–93.CrossRefGoogle Scholar
- 20.Kazumori H, Ishihara S, Hoshino E, Kawashima K, Moriyama N, Suetsugu H, et al. Neutrophil chemoattractant 2β regulates expression of the Reg gene in injured gastric mucosa in rats. Gastroenterology. 2000;119:1610–22.CrossRefGoogle Scholar
- 21.Peterson KM, Guo X, Elkahloun AG, Mondal D, Bardhan PK, Sugawara A, et al. The expression of REG 1A and REG 1B is increased during acute amebic colitis. Parasitol Int. 2011;60:296–300.CrossRefGoogle Scholar
- 22.Sugimoto K, Ogawa A, Mizoguchi E, et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest. 2008;118:534–44.PubMedPubMedCentralGoogle Scholar
- 23.Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q, et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med. 2008;14:282–9.CrossRefGoogle Scholar
- 24.Sekikawa A, Fukui H, Suzuki K, Karibe T, Fujii S, Ichikawa K, et al. Involvement of the IL-22/REG Iα axis in ulcerative colitis. Lab Investig. 2010;90:496–505.CrossRefGoogle Scholar
- 25.Waldner MJ, Neurath MF. Master regulator of intestinal disease: IL-6 in chronic inflammation and cancer development. Semin Immunol. 2014;26:75–9.CrossRefGoogle Scholar