Pathophysiological significance of the two-pore domain K(+) channel K2P5.1 in splenic CD4(+)CD25(-) T cell subset from a chemically-induced murine inflammatory bowel disease model.

The alkaline pH-activated, two-pore domain K(+) channel K2P5.1 (also known as TASK2/KCNK5) plays an important role in maintaining the resting membrane potential, and contributes to the control of Ca(2+) signaling in several types of cells. Recent studies highlighted the potential role of the K2P5.1 K(+) channel in the pathogenesis of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. The aim of the present study was to elucidate the pathological significance of the K2P5.1 K(+) channel in inflammatory bowel disease (IBD). The degrees of colitis, colonic epithelial damage, and colonic inflammation were quantified in the dextran sulfate sodium-induced mouse IBD model by macroscopic and histological scoring systems. The expression and functional activity of K2P5.1 in splenic CD4(+) T cells were measured using real-time PCR, Western blot, and fluorescence imaging assays. A significant increase was observed in the expression of K2P5.1 in the splenic CD4(+) T cells of the IBD model. Concomitant with this increase, the hyperpolarization response induced by extracellular alkaline pH was significantly larger in the IBD model with the corresponding intracellular Ca(2+) rises. The expression of K2P5.1 was higher in CD4(+)CD25(-) T cells than in CD4(+)CD25(+) regulatory T cells. The knockout of K2P5.1 in mice significantly suppressed the disease responses implicated in the IBD model. Alternations in intracellular Ca(2+) signaling following the dysregulated expression of K2P5.1 were associated with the disease pathogenesis of IBD. The results of the present study suggest that the K2P5.1 K(+) channel in CD4(+)CD25(-) T cell subset is a potential therapeutic target and biomarker for IBD.

Upregulation of KCa3.1 K(+) channel in mesenteric lymph node CD4(+) T lymphocytes from a mouse model of dextran sodium sulfate-induced inflammatory bowel disease.

The intermediate-conductance Ca(2+)-activated K(+) channel KCa3.1/KCNN4 plays an important role in the modulation of Ca(2+) signaling through the control of the membrane potential in T lymphocytes. Here, we study the involvement of KCa3.1 in the enlargement of the mesenteric lymph nodes (MLNs) in a mouse model of inflammatory bowel disease (IBD). The mouse model of IBD was prepared by exposing male C57BL/6J mice to 5% dextran sulfate sodium for 7 days. Inflammation-induced changes in KCa3.1 activity and the expressions of KCa3.1 and its regulators in MLN CD4(+) T lymphocytes were monitored by real-time PCR, Western blot, voltage-sensitive dye imaging, patch-clamp, and flow cytometric analyses. Concomitant with an upregulation of KCa3.1a and nucleoside diphosphate kinase B (NDPK-B), a positive KCa3.1 regulator, an increase in KCa3.1 activity was observed in MLN CD4(+) T lymphocytes in the IBD model. Pharmacological blockade of KCa3.1 elicited the following results: 1) a significant decrease in IBD disease severity, as assessed by diarrhea, visible fecal blood, inflammation, and crypt damage of the colon and MLN enlargement compared with control mice, and 2) the restoration of the expression levels of KCa3.1a, NDPK-B, and Th1 cytokines in IBD model MLN CD4(+) T lymphocytes. These findings suggest that the increase in KCa3.1 activity induced by the upregulation of KCa3.1a and NDPK-B may be involved in the pathogenesis of IBD by mediating the enhancement of the proliferative response in MLN CD4(+) T lymphocyte and, therefore, that the pharmacological blockade of KCa3.1 may decrease the risk of IBD.