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Research ArticleCellular and Molecular

Increased Interleukin-10 Expression by the Inhibition of Ca2+-Activated K+ Channel KCa3.1 in CD4+CD25+ Regulatory T Cells in the Recovery Phase in an Inflammatory Bowel Disease Mouse Model

Susumu Ohya, Miki Matsui, Junko Kajikuri, Kyoko Endo and Hiroaki Kito
Journal of Pharmacology and Experimental Therapeutics April 2021, 377 (1) 75-85; DOI: https://doi.org/10.1124/jpet.120.000395
Susumu Ohya
Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
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Miki Matsui
Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
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Junko Kajikuri
Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
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Kyoko Endo
Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
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Hiroaki Kito
Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
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Abstract

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 CD4+CD25+ regulatory T (Treg) cells play a protective role in the recovery phase of IBD. In the present study, the effects of the administration of the selective Ca2+-activated K+ channel KCa3.1 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 KCa3.1 in mesenteric lymph node (mLN) Treg 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 KCa3.1 in the mLN Treg cells of IBD model mice. In mouse peripheral CD4+CD25+ Treg 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 KCa3.1 decreased IBD symptoms in the IBD model by increasing IL-10 production in peripheral Treg cells and that IL-10high Treg cells produced by the treatment with KCa3.1 inhibitor may contribute to efficient Treg therapy for chronic inflammatory disorders, including IBD.

SIGNIFICANCE STATEMENT Pharmacological inhibition of Ca2+-activated K+ channel KCa3.1 increased IL-10 expression in peripheral Treg 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-10high–producing Treg cells by the pharmacological inhibition of KCa3.1 may be beneficial in the treatment of chronic inflammatory diseases such as inflammatory bowel disease.

Footnotes

    • Received October 23, 2020.
    • Accepted January 22, 2021.
  • ↵1 S.O. and M.M. contributed equally to this work.

  • This work was supported by a Grant-in-Aid for Scientific Research (C) [16K-8285], a Grant-in-Aid for Fostering Joint International Research (B) [18KK0218] by the Japan Society for the Promotion of Science (JSPS), and a grant from the Bristol-Myers Squibb foundation [53952417].

  • The authors declare no conflicts of interest associated with this manuscript.

  • https://doi.org/10.1124/jpet.120.000395.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 377 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 377, Issue 1
1 Apr 2021
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Research ArticleCellular and Molecular

Increased IL-10 by KCa3.1 Inhibition in Treg Cells

Susumu Ohya, Miki Matsui, Junko Kajikuri, Kyoko Endo and Hiroaki Kito
Journal of Pharmacology and Experimental Therapeutics April 1, 2021, 377 (1) 75-85; DOI: https://doi.org/10.1124/jpet.120.000395

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Research ArticleCellular and Molecular

Increased IL-10 by KCa3.1 Inhibition in Treg Cells

Susumu Ohya, Miki Matsui, Junko Kajikuri, Kyoko Endo and Hiroaki Kito
Journal of Pharmacology and Experimental Therapeutics April 1, 2021, 377 (1) 75-85; DOI: https://doi.org/10.1124/jpet.120.000395
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