title: Expression of T-cell KV1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis.
abstract: OBJECTIVE
  Potassium channels, KV1.3 and KCa3.1, have been suggested to control T-cell activation, proliferation, and cytokine production and may thus constitute targets for anti-inflammatory therapy. Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by excessive T-cell infiltration and cytokine production. It is unknown if KV1.3 and KCa3.1 in the inflamed mucosa are markers of active UC. We hypothesized that KV1.3 and KCa3.1 correlate with disease activity and cytokine production in patients with UC.
  
  
  METHODS
  Mucosal biopsies were collected from patients with active UC (n=33) and controls (n=15). Protein and mRNA expression of KV1.3 and KCa3.1, immune cell markers, and pro-inflammatory cytokines were determined by quantitative-real-time-polymerase-chain-reaction (qPCR) and immunofluorescence, and correlated with clinical parameters of inflammation. In-vitro cytokine production was measured in human CD3(+) T-cells after pharmacological blockade of KV1.3 and KCa3.1.
  
  
  RESULTS
  Active UC KV1.3 mRNA expression was increased 5-fold compared to controls. Immunofluorescence analyses revealed that KV1.3 protein was present in inflamed mucosa in 57% of CD4(+) and 23% of CD8(+) T-cells. KV1.3 was virtually absent on infiltrating macrophages. KV1.3 mRNA expression correlated significantly with mRNA expression of pro-inflammatory cytokines TNF-α (R(2)=0.61) and IL-17A (R(2)=0.51), the mayo endoscopic subscore (R(2)=0.13), and histological inflammation (R(2)=0.23). In-vitro blockade of T-cell KV1.3 and KCa3.1 decreased production of IFN-γ, TNF-α, and IL-17A.
  
  
  CONCLUSIONS
  High levels of KV1.3 in CD4 and CD8 positive T-cells infiltrates are associated with production of pro-inflammatory IL-17A and TNF-α in active UC. KV1.3 may serve as a marker of disease activity and pharmacological blockade might constitute a novel immunosuppressive strategy.
authors.affiliation: Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology, Hospital of Southwest Jutland, Esbjerg, Denmark. Electronic address: larskochhansen@dadlnet.dk.
authors.forename: Lars
authors.initials: L
authors.lastname: Koch Hansen
authors.affiliation: Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; Department of Gastroenterology, Odense University Hospital, Denmark. Electronic address: lmoeller@health.sdu.dk.
authors.forename: Linda
authors.initials: L
authors.lastname: Sevelsted-Møller
authors.affiliation: Department of Pathology, Odense University Hospital, Denmark. Electronic address: missrabjerg@gmail.com.
authors.forename: Maj
authors.initials: M
authors.lastname: Rabjerg
authors.affiliation: Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark. Electronic address: larsen.dorte@gmail.com.
authors.forename: Dorte
authors.initials: D
authors.lastname: Larsen
authors.affiliation: Department of Pathology, Odense University Hospital, Denmark. Electronic address: tine.hansen@rsyd.dk.
authors.forename: Tine Plato
authors.initials: TP
authors.lastname: Hansen
authors.affiliation: Department of Gastroenterology, Odense University Hospital, Denmark. Electronic address: klinge@dadlnet.dk.
authors.forename: Lone
authors.initials: L
authors.lastname: Klinge
authors.affiliation: Department of Pharmacology, University of CA, Davis, USA. Electronic address: hwulff@ucdavis.edu.
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.affiliation: Department of Gastroenterology, Hospital of Southwest Jutland, Esbjerg, Denmark. Electronic address: torben.knudsen@rsyd.dk.
authors.forename: Torben
authors.initials: T
authors.lastname: Knudsen
authors.affiliation: Department of Gastroenterology, Odense University Hospital, Denmark. Electronic address: jens.kjeldsen@rsyd.dk.
authors.forename: Jens
authors.initials: J
authors.lastname: Kjeldsen
authors.affiliation: Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; Aragon Institute of Health Sciences & IIS and Fundación Agencia Aragonesa para la Investigación y Desarrollo (ARAID), 50009 Zaragoza, Spain. Electronic address: rkohler.iacs@aragon.es.
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhler
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003430:Cross-Sectional Studies; D005260:Female; D015870:Gene Expression; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008214:Lymphocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D014320:Triphenylmethyl Compounds / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000081:Acetamides; D015415:Biomarkers; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D020381:Interleukin-17; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D051664:Kv1.3 Potassium Channel; D012333:RNA, Messenger; D017452:Receptors, IgG; D014320:Triphenylmethyl Compounds; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C472774:senicapoc
keywords: Colitis ulcerosa;; Interleukins;; K(Ca)3.1; KCNA3;; KCNN4;; Novel treatment strategy;