Expression of T-cell K<inf>V</inf>1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis

Lars Koch Hansen, Linda Sevelsted-Møller, Maj Rabjerg, Dorte Larsen, Tine Plato Hansen, Lone Klinge, Heike Wulff, Torben Knudsen, Jens Kjeldsen, Ralf Köhler

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19 Scopus citations

Abstract

Background and aims: Potassium channels, K<inf>V</inf>1.3 and K<inf>Ca</inf>3.1, 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 K<inf>V</inf>1.3 and K<inf>Ca</inf>3.1 in the inflamed mucosa are markers of active UC. We hypothesized that K<inf>V</inf>1.3 and K<inf>Ca</inf>3.1 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 K<inf>V</inf>1.3 and K<inf>Ca</inf>3.1, 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<sup>+</sup> T-cells after pharmacological blockade of K<inf>V</inf>1.3 and K<inf>Ca</inf>3.1. Results: Active UC K<inf>V</inf>1.3 mRNA expression was increased 5-fold compared to controls. Immunofluorescence analyses revealed that K<inf>V</inf>1.3 protein was present in inflamed mucosa in 57% of CD4<sup>+</sup> and 23% of CD8<sup>+</sup> T-cells. K<inf>V</inf>1.3 was virtually absent on infiltrating macrophages. K<inf>V</inf>1.3 mRNA expression correlated significantly with mRNA expression of pro-inflammatory cytokines TNF-α (R<sup>2</sup>=0.61) and IL-17A (R<sup>2</sup>=0.51), the mayo endoscopic subscore (R<sup>2</sup>=0.13), and histological inflammation (R<sup>2</sup>=0.23). In-vitro blockade of T-cell K<inf>V</inf>1.3 and K<inf>Ca</inf>3.1 decreased production of IFN-γ, TNF-α, and IL-17A. Conclusions: High levels of K<inf>V</inf>1.3 in CD4 and CD8 positive T-cells infiltrates are associated with production of pro-inflammatory IL-17A and TNF-α in active UC. K<inf>V</inf>1.3 may serve as a marker of disease activity and pharmacological blockade might constitute a novel immunosuppressive strategy.

Original languageEnglish (US)
Pages (from-to)1378-1391
Number of pages14
JournalJournal of Crohn's and Colitis
Volume8
Issue number11
DOIs
StatePublished - 2014

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Keywords

  • Colitis ulcerosa;
  • Interleukins;
  • K<inf>Ca</inf>3.1
  • KCNA3;
  • KCNN4;
  • Novel treatment strategy;

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Koch Hansen, L., Sevelsted-Møller, L., Rabjerg, M., Larsen, D., Hansen, T. P., Klinge, L., Wulff, H., Knudsen, T., Kjeldsen, J., & Köhler, R. (2014). Expression of T-cell K<inf>V</inf>1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis. Journal of Crohn's and Colitis, 8(11), 1378-1391. https://doi.org/10.1016/j.crohns.2014.04.003