title: Interleukin-6 induces S100A9 expression in colonic epithelial cells through STAT3 activation in experimental ulcerative colitis.
abstract: BACKGROUND
  Intestinal epithelium is essential for maintaining normal intestinal homeostasis; its breakdown leads to chronic inflammatory pathologies, such as inflammatory bowel diseases (IBDs). Although high concentrations of S100A9 protein and interleukin-6 (IL-6) are found in patients with IBD, the expression mechanism of S100A9 in colonic epithelial cells (CECs) remains elusive. We investigated the role of IL-6 in S100A9 expression in CECs using a colitis model.
  
  
  METHODS
  IL-6 and S100A9 expression, signal transducer and activator of transcription 3 (STAT3) phosphorylation, and infiltration of immune cells were analyzed in mice with dextran sulfate sodium (DSS)-induced colitis. The effects of soluble gp130-Fc protein (sgp130Fc) and S100A9 small interfering (si) RNA (si-S100A9) on DSS-induced colitis were evaluated. The molecular mechanism of S100A9 expression was investigated in an IL-6-treated Caco-2 cell line using chromatin immunoprecipitation assays.
  
  
  RESULTS
  IL-6 concentrations increased significantly in the colon tissues of DSS-treated mice. sgp130Fc or si-S100A9 administration to DSS-treated mice reduced granulocyte infiltration in CECs and induced the down-regulation of S100A9 and colitis disease activity. Treatment with STAT3 inhibitors upon IL-6 stimulation in the Caco-2 cell line demonstrated that IL-6 mediated S100A9 expression through STAT3 activation. Moreover, we found that phospho-STAT3 binds directly to the S100A9 promoter. S100A9 may recruit immune cells into inflamed colon tissues.
  
  
  CONCLUSIONS
  Elevated S100A9 expression in CECs mediated by an IL-6/STAT3 signaling cascade may play an important role in the development of colitis.
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Min Jeoung
authors.initials: MJ
authors.lastname: Lee
authors.forename: Jin-Ku
authors.initials: JK
authors.lastname: Lee
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Choi
authors.forename: Chang-Seok
authors.initials: CS
authors.lastname: Lee
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Sim
authors.forename: Chung-Hyun
authors.initials: CH
authors.lastname: Cho
authors.forename: Kwang-Ho
authors.initials: KH
authors.lastname: Lee
authors.forename: Ik-Hyun
authors.initials: IH
authors.lastname: Cho
authors.forename: Myung-Hee
authors.initials: MH
authors.lastname: Chung
authors.forename: Hang-Rae
authors.initials: HR
authors.lastname: Kim
authors.forename: Sang-Kyu
authors.initials: SK
authors.lastname: Ye
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D040502:Calgranulin B; D015850:Interleukin-6; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D050822:Cytokine Receptor gp130; D016264:Dextran Sulfate