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

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⁺ 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⁺ and 23% of CD8⁺ 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 (R²=0.61) and IL-17A (R²=0.51), the mayo endoscopic subscore (R²=0.13), and histological inflammation (R²=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.