title: Pro-inflammatory miR-223 mediates the cross-talk between the IL23 pathway and the intestinal barrier in inflammatory bowel disease.
abstract: BACKGROUND
  The IL23/Th17 pathway is essential for the onset of inflammatory bowel disease (IBD), yet the specific mechanism by which this pathway initiates the disease remains unknown. In this study, we identify the mechanisms that mediate cross-talk between the IL23 pathway and the intestinal barrier in IBD.
  
  
  RESULTS
  The downstream targets of the IL23 pathway were identified by RNA array profiling and confirmed by immunohistochemical staining. The role of miRNAs that interact with IL23 was explored in mice with TNBS-induced colitis. Claudin-8 (CLDN8), a multigene family protein that constitutes the backbone of tight junctions, was identified as a novel target of IL23 in IBD. CLDN8 was significantly downregulated in IBD patients with inflamed colonic mucosa, and in trinitrobenzene sulphonic acid (TNBS) induced colitis in mice. Therapeutic treatment of colitis in mice using an IL23 antibody restored CLDN8 abundance, in parallel with recovery from colitis. In addition, we identify miR-223 as a novel mediator of the crosstalk between the IL23 signal pathway and CLDN8 in the development of IBD. MiR-223 was upregulated in IBD, and its activity was regulated through the IL23 pathway. Antagomir inhibition of miR-223 reactivated CLDN8 and improved a number of signs associated with TNBS-induced colitis in mice.
  
  
  CONCLUSIONS
  Our study characterizes a new mechanistic pathway in IBD, in which miR-223 interacts with the IL23 pathway by targeting CLDN8. Strategies designed to disrupt this interaction may provide novel therapeutic agents for the management of IBD.
authors.affiliation: Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Road 2, Guangzhou, 510080, P.R. China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Road 2, Guangzhou, 510080, P.R. China.
authors.forename: Kang
authors.initials: K
authors.lastname: Chao
authors.affiliation: Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Science, Hong Kong, P.R. China.
authors.forename: Siew Chien
authors.initials: SC
authors.lastname: Ng
authors.affiliation: Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Science, Hong Kong, P.R. China.
authors.forename: Alfa Hc
authors.initials: AH
authors.lastname: Bai
authors.affiliation: Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Road 2, Guangzhou, 510080, P.R. China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Institute of Digestive Disease, Li Ka Shing Institute of Health Science, Hong Kong, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.affiliation: Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Road 2, Guangzhou, 510080, P.R. China.
authors.forename: Manying
authors.initials: M
authors.lastname: Li
authors.affiliation: Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Road 2, Guangzhou, 510080, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Road 2, Guangzhou, 510080, P.R. China. chenminhu@vip.163.com.
authors.forename: Minhu
authors.initials: M
authors.lastname: Chen
authors.affiliation: Stem Cell and Cancer Center, First Hospital, Jilin University, Changchun, P.R. China. jifan@stanford.edu.|Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA, 94304, USA. jifan@stanford.edu.
authors.forename: Ji-Fan
authors.initials: JF
authors.lastname: Hu
authors.affiliation: Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Road 2, Guangzhou, 510080, P.R. China. shenghongzhang@163.com.
authors.forename: Shenghong
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000070416:Antagomirs; D018938:Caco-2 Cells; D002460:Cell Line; D057167:Claudins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D053759:Interleukin-23 / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D009841:Oligonucleotides / Q000008:administration & dosage / Q000627:therapeutic use; D015398:Signal Transduction; D014302:Trinitrobenzenesulfonic Acid / Q000009:adverse effects
chemical_list: D000070416:Antagomirs; D057167:Claudins; D053759:Interleukin-23; D035683:MicroRNAs; D009841:Oligonucleotides; D014302:Trinitrobenzenesulfonic Acid; C525067:MIR223, human; C000603521:antagomir-223; C502011:claudin 8
keywords: Crohn’s disease; Interleukin 23; Pathway; Ulcerative colitis; miRNA