title: Anti-apoptotic effect of interleukin-22 on fibroblast-like synoviocytes in patients with rheumatoid arthritis is mediated via the signal transducer and activator of transcription 3 signaling pathway.
abstract: OBJECTIVE
  Inadequate apoptosis of fibroblast-like synoviocytes (FLS) plays a crucial role in the immunopathogenesis of rheumatoid arthritis (RA). Interleukin-22 (IL-22) is a novel member of the cytokine network that has been found to be involved in the immunological process underlying RA. In this study, we investigated the effect of IL-22 on the survival of RA-FLS from RA patients and examined the possible mechanism to determine new therapeutic strategies for RA.
  
  
  METHODS
  FLS obtained from patients with RA were cultured in vitro and treated with sodium nitroprussiate (SNP) to induce apoptosis in the presence or absence of IL-22. RA-FLS viability was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RA-FLS apoptosis was analyzed by annexin V/propidium iodide staining (AV/PI). The levels of IL-22R1, pSTAT3-Y705, pSTAT3-S727, total STAT3, Bcl-xL and Bcl-2 were detected by Western blot analysis.
  
  
  RESULTS
  IL-22R1 was expressed on RA-FLS. IL-22 pretreatment at concentrations ranging from 10 to 100 ng/mL increased RA-FLS viability and prevented SNP-induced apoptosis. Treatment with the STAT3 inhibitors, HO3867 or STA21, reversed the protective effect of IL-22 on SNP-induced apoptosis of RA-FLS. IL-22-induced phosphorylation of STAT3 (pSTAT3-Y705 and pSTAT3-S727) was increased in RA-FLS. Also IL-22 increased Bcl-2 expression in SNP-treated RA-FLS, and the effect was reversed by treatment with HO3867 or STA21.
  
  
  CONCLUSIONS
  IL-22 protects against SNP-induced apoptosis in RA-FLS by activating the STAT3 pathway and the downstream target gene, Bcl-2. Therefore, therapeutic strategies that target the IL-22/STAT3 pathway are implicated as candidates for RA treatment.
authors: Department of Rheumatology, The First Affiliated Hospital of China Medical University, Shenyang, China.|Department of Rheumatology, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors: Min
authors: M
authors: Zhao
authors: Department of Rheumatology, The First Affiliated Hospital of China Medical University, Shenyang, China.
authors: Yishuo
authors: Y
authors: Li
authors: Department of Rheumatology, The First Affiliated Hospital of China Medical University, Shenyang, China.
authors: Weiguo
authors: W
authors: Xiao
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection; D056945:Hep G2 Cells; D006801:Humans; D007378:Interleukins / Q000494:pharmacology*; D008875:Middle Aged; D009599:Nitroprusside / Q000633:toxicity; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000070918:Synoviocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D009599:Nitroprusside; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; D000097043:Interleukin-22; C000595707:BCL2 protein, human; C494086:STAT3 protein, human
keywords: IL-22; RA-FLS; STAT3; apoptosis