title: High suppressor of cytokine signaling-3 expression impairs STAT3-dependent protective effects of interleukin-22 in ulcerative colitis in remission.
abstract: BACKGROUND
  High SOCS3 expression in intestinal epithelial cells (IECs) of patients with ulcerative colitis (UC) in remission reflects the shorter time to relapse. We investigated whether high SOCS3 increased risk for relapse through violating STAT3-dependent protective effects of interleukin (IL)-22 during UC remission.
  
  
  METHODS
  Expression of IL-22 and c-Myc in UC remission mucosa was analyzed by immunohistochemistry. Effects of IL-22 on migration and proliferation of IEC cell lines with enforced SOCS3 expression were assessed with wounding assay and CCK-8 assay, respectively. Influence of STAT3 interference and SOCS3 overexpression on IL-22-regulated expression of antimicrobial peptide and proliferation-related molecules, including DMBT1, c-Myc, Survivin, Bcl-2, and Bcl-xL, were performed with quantitative real-time polymerase chain reaction or Western blot.
  
  
  RESULTS
  Patients with UC in remission showed significantly more IL-22-positive immune cells, but no difference of epithelial c-Myc levels, in mucosa compared with healthy controls. Overexpression of SOCS3 nearly abolished IL-22-induced activation of STAT3. By inhibiting STAT3 signaling, SOCS3 influenced IL-22-induced expression of DMBT1, c-Myc, Survivin, and Bcl-2 as well as proliferation and migration processes in cultured IEC cell line.
  
  
  CONCLUSIONS
  SOCS3 overexpression impairs IL-22-mediated epithelial homeostasis and mucosal wound healing, which could be the mechanism for high SOCS3 IEC expression contributed early relapse of mucosal inflammation. Prevention of SOCS3 expression or enhancement of IL-22/STAT3 signaling in IEC seems to be rational therapeutic strategies for UC remission maintenance.
authors.affiliation: Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: An Tao
authors.initials: AT
authors.lastname: Xu
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
authors.forename: Xi Tao
authors.initials: XT
authors.lastname: Xu
authors.forename: Yu Qi
authors.initials: YQ
authors.lastname: Qiao
authors.forename: Ming Ming
authors.initials: MM
authors.lastname: Zhu
authors.forename: Tian Rong
authors.initials: TR
authors.lastname: Wang
authors.forename: Yun
authors.initials: Y
authors.lastname: Cui
authors.forename: Luo Yan
authors.initials: LY
authors.lastname: Ai
authors.forename: Zhi Hua
authors.initials: ZH
authors.lastname: Ran
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016022:Case-Control Studies; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000097043:Interleukin-22; C106644:SOCS3 protein, human; C494086:STAT3 protein, human