title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan; Department of Molecular & Cellular Pharmacology, Nagoya City University, Nagoya, Japan; sohya@mb.kyoto-phu.ac.jp.
authors.forename: Susumu
authors.initials: S
authors.lastname: Ohya
authors.affiliation: Department of Molecular & Cellular Pharmacology, Nagoya City University, Nagoya, Japan;
authors.forename: Yuka
authors.initials: Y
authors.lastname: Fukuyo
authors.affiliation: Department of Molecular & Cellular Pharmacology, Nagoya City University, Nagoya, Japan;
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kito
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan;
authors.forename: Rina
authors.initials: R
authors.lastname: Shibaoka
authors.affiliation: Department of Molecular & Cellular Pharmacology, Nagoya City University, Nagoya, Japan;
authors.forename: Miki
authors.initials: M
authors.lastname: Matsui
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan;
authors.forename: Hiroki
authors.initials: H
authors.lastname: Niguma
authors.affiliation: Department of Hospital Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan; and.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Department of Molecular & Cellular Pharmacology, Nagoya City University, Nagoya, Japan;
authors.forename: Hisao
authors.initials: H
authors.lastname: Yamamura
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan;
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujii
authors.affiliation: Department of Hospital Pharmacy, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan; and Department of Clinical Pharmacy, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kimura
authors.affiliation: Department of Molecular & Cellular Pharmacology, Nagoya City University, Nagoya, Japan;
authors.forename: Yuji
authors.initials: Y
authors.lastname: Imaizumi
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054778:NM23 Nucleoside Diphosphate Kinases / Q000096:biosynthesis*; D009687:Nuclear Proteins / Q000096:biosynthesis; D011720:Pyrazoles / Q000627:therapeutic use; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation; D000070584:Tripartite Motif Proteins
chemical_list: D004268:DNA-Binding Proteins; D016264:Dextran Sulfate; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D054778:NM23 Nucleoside Diphosphate Kinases; D009687:Nuclear Proteins; D011720:Pyrazoles; D044767:Ubiquitin-Protein Ligases; C496925:Kcnn4 protein, mouse; C411671:TRAM 34; C489296:Trim27 protein, mouse; D000070584:Tripartite Motif Proteins; C517941:Nme2 protein, mouse
keywords: CD4+ T lymphocyte; KCa3.1; TRAM-34; inflammatory bowel disease; mesenteric lymph node