title: Forkhead box protein 3 in human nasal polyp regulatory T cells is regulated by the protein suppressor of cytokine signaling 3.
abstract: BACKGROUND
  In patients with persistent upper airway inflammation, the number of forkhead box protein 3 (Foxp3)(+) regulatory T (Treg) cells is reduced, but the regulation of Foxp3 expression in Treg cells is poorly understood.
  
  
  OBJECTIVE
  We investigated the interaction between suppressor of cytokine signaling 3 (SOCS3) and Foxp3 expression in the airway mucosa.
  
  
  METHODS
  Expression of SOCS3 and Foxp3 was measured in tissue from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and control tissue. Coexpression of SOCS3 and Foxp3 was evaluated in PBMCs and in tissue from patients with CRSwNP. We also switched off and overexpressed SOCS3 in tissue from patients with CRSwNP and in pancreatic carcinoma epithelial-like cell line (PANC-1) cells and examined the effect on Foxp3 expression.
  
  
  RESULTS
  SOCS3 gene and protein expression was upregulated in inflammatory cells in airway mucosa, whereas Foxp3 gene and protein expression was downregulated. Mucosal Treg cells coexpressed both proteins. Switching off the expression of SOCS3 in human airway mucosa resulted in Foxp3 upregulation, whereas inducing it in PANC-1 cells led to Foxp3 downregulation. We also found that phosphorylation of signal transducer and activator of transcription (STAT) 3 was decreased in inflamed mucosa, and we hypothesized that SOCS3 was responsible. Phosphorylation of STAT3 increased on silencing SOCS3 expression in inflamed mucosa and decreased on SOCS3 plasmid transfection in PANC-1 cells.
  
  
  CONCLUSIONS
  For the first time, we demonstrate that SOCS3 and Foxp3 are coexpressed in Treg cells in human nasal mucosa and that SOCS3 negatively regulates Foxp3 expression in human airway mucosa, possibly through phosphorylation of STAT3. Hence SOCS3 could be a potential target for restoring Foxp3 expression in Treg cells in patients with persistent mucosal inflammation.
authors.affiliation: Division of Geriatrics, Center for Medical Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Upper Airways Research Laboratory, ENT Department, Ghent University, Ghent, Belgium.
authors.forename: Feng
authors.initials: F
authors.lastname: Lan
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Olga
authors.initials: O
authors.lastname: Krysko
authors.forename: Quanbo
authors.initials: Q
authors.lastname: Zhang
authors.forename: Junming
authors.initials: J
authors.lastname: Xian
authors.forename: Lara
authors.initials: L
authors.lastname: Derycke
authors.forename: Yanyu
authors.initials: Y
authors.lastname: Qi
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.forename: Shixi
authors.initials: S
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Lin
authors.forename: Claus
authors.initials: C
authors.lastname: Bachert
mesh_terms: D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins; D045744:Cell Line, Tumor; D002908:Chronic Disease; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009297:Nasal Mucosa / Q000276:immunology; D009298:Nasal Polyps / Q000276:immunology*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D012220:Rhinitis / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012852:Sinusitis / Q000276:immunology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019076:Transgenes / Q000235:genetics; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins
keywords: APC; Antigen-presenting cell; CRSwNP; Chronic rhinosinusitis with nasal polyps; Forkhead box protein 3; Foxp3; JAK; Janus kinase; PANC-1; Pancreatic carcinoma epithelial-like cell line; Phosphorylated signal transducer and activator of transcription; Regulatory T; SOCS3; STAT; Signal transducer and activator of transcription; Small interfering RNA; Suppressor of cytokine signaling 3; Treg; airway disease; nasal polyps; pSTAT; siRNA; signal transducer and activator of transcription 3; suppressor of cytokine signaling 3