Dextran sodium sulfate (DSS)-induced rodent colitis models are widely used as a model system for examining IBD (Inflammatory Bowel Disease) pathogenesis including ulcerative colitis and Crohn’s disease. Genome expression profile analysis during the development of DSS-induced IBD model showed correlation with IBD patient data. The intermediate-conductance Ca2+-activated K,sup>+ channel, KCa3.1 plays an important role for the modification of Ca2+ signaling through the control of the membrane potential in T-lymphocytes, and KCa3.1 can be a potential target for therapeutic strategies of IBD (Di et al., 2010; Simms et al., 2010). However, pathophysiological impact of KCa3.1 on the immune dysfunction in mucosal lymphoid tissue of IBD model animals remains to be determined. Here, the involvement of KCa3.1 in the enlargement of mesenteric lymph node (MLN) on the pathogenesis of mice IBD model was investigated. Mice IBD model was prepared by exposing male C57BL/6 mice to 5 % dextran sulfate sodium (DSS) for 7 days. All animal experiments were carried out in accordance with the guiding principles for the care and use of laboratory animals in Kyoto Pharmaceutical University and Nagoya City University. Inflammation-induced changes in KCa3.1 activity, the expressions of KCa3.1 and its regulators, and the cell-cycle distribution in MLN CD4+ T-lymphocytes were monitored by real-time PCR, Western blot, voltage-sensitive dye imaging, and flow cytometry analyses. Concomitantly with the up-regulation of KCa3.1a and nucleoside diphosphate kinase B (NDPK-B), the increase in KCa3.1 activity was observed in MLN CD4+ T-lymphocytes of DSS-induced IBD model. Pharmacological blockade of KCa3.1 produced 1) the significant decrease in disease severities in IBD model, and MLN enlargement, compared with the control mice (n=17), 2) the restoration of the expressions of KCa3.1a, NDPK-B, and Th1 cytokines in MLN CD4+ T-lymphocytes of IBD model (n=4-6), 3) the arrest of both G1/S and G2/M transitions during cell-cycle progression in MLN CD4+ T-lymphocytes of IBD model (n=8), and 4) the inhibition of interleukin-6 (IL-6) production in the inflamed tissues (n=4). In addition, tripartite motif containing protein 27 (TRIM27), which suppresses the KCa3.1 activity through the polyubiquitination of PI3K-C2β, was significantly increased in MLN CD4+ T-lymphocytes of IBD model (n=6), suggesting that the up-regulation of TRIM-27 may be a compensatory mechanism in CD4+ T-lymphocyte activation in IBD patients. These suggest that the increase in KCa3.1 activity through the up-regulation of KCa3.1a/NDPK-B complex may be involved in the pathogenesis of IBD via the enhancement of MLN CD4+ T-lymphocyte proliferation. Pharmacological blockade of KCa3.1 may decrease the risk of IBD development.