Expression of T-cell KV1.3 potassium channel correlates with pro-inflammatory cytokines and disease activity in ulcerative colitis

Background and aims: Potassium channels, K(v)1.3 and K(Ca)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(V)1.3 and K(Ca)3.1 in the inflamed mucosa are markers of active UC. We hypothesized that K(V)1.3 and K(Ca)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(v)1.3 and K(Ca)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 CDr T-cells after pharmacological blockade of K(V)1.3 and K(Ca)3.1. Results: Active UC K(V)1.3 mRNA expression was increased 5-fold compared to controls. Immunofluorescence analyses revealed that K(v)1.3 protein was present in inflamed mucosa in 57% of CD4(+) and 23% of CD8(+) T-cells. K(V)1.3 was virtually absent on infiltrating macrophages. K(V)1.3 mRNA expression correlated significantly with mRNA expression of pro-inflammatory cytokines TNF-alpha (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 K(V)1.3 and K(Ca)3.1 decreased production of IFN-gamma, TNF-alpha, and IL-17A. Conclusions: High levels of K(V)1.3 in CD4 and CD8 positive T-cells infiltrates are associated with production of pro-inflammatory IL-17A and TNF-alpha in active UC. K(V)1.3 may serve as a marker of disease activity and pharmacological blockade might constitute a novel immunosuppressive strategy. (C) 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.