Increased Interleukin-10 Expression by the Inhibition of Ca-Activated K Channel K3.1 in CD4CD25 Regulatory T Cells in the Recovery Phase in an Inflammatory Bowel Disease Mouse Model.

Inflammatory bowel diseases (IBD) are chronic inflammatory diseases of the gastrointestinal tract arising from abnormal responses of the innate and adaptative immune systems. Interleukin (IL)-10-producing CD4CD25 regulatory T (T) cells play a protective role in the recovery phase of IBD. In the present study, the effects of the administration of the selective Ca-activated K channel K3.1 inhibitor TRAM-34 on disease activities were examined in chemically induced IBD model mice. IBD disease severity, as assessed by diarrhea, visible fecal blood, inflammation, and crypt damage in the colon, was significantly lower in mice administered 1 mg/kg TRAM-34 than in vehicle-administered mice. Quantitative real-time polymerase chain reaction examinations showed that IL-10 expression levels in the recovery phase were markedly increased by the inhibition of K3.1 in mesenteric lymph node (mLN) T cells of IBD model mice compared with vehicle-administered mice. Among several positive and negative transcriptional regulators (TRs) for IL-10, three positive TRs-E4BP4, KLF4, and Blimp1-were upregulated by the inhibition of K3.1 in the mLN T cells of IBD model mice. In mouse peripheral CD4CD25 T cells induced by lectin stimulation, IL-10 expression and secretion were enhanced by the treatment with TRAM-34, together with the upregulation of E4BP4, KLF4, and Blimp1. Collectively, the present results demonstrated that the pharmacological inhibition of K3.1 decreased IBD symptoms in the IBD model by increasing IL-10 production in peripheral T cells and that IL-10 T cells produced by the treatment with K3.1 inhibitor may contribute to efficient T therapy for chronic inflammatory disorders, including IBD. SIGNIFICANCE STATEMENT: Pharmacological inhibition of Ca-activated K channel K3.1 increased IL-10 expression in peripheral T cells, together with the upregulation of the transcriptional regulators of IL-10: Krüppel-like factor 4, E4 promoter-binding protein 4, and/or B lymphocyte-induced maturation protein 1. The manipulation of IL-10-producing T cells by the pharmacological inhibition of K3.1 may be beneficial in the treatment of chronic inflammatory diseases such as inflammatory bowel disease.