<i>Clock</i>-dependent temporal regulation of IL-33/ST2-mediated mast cell response

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Author(s)

    • Ishimaru Kayoko
    • Department of Immunology, University of Yamanashi Faculty of Medicine
    • Nakamura Yuki
    • Department of Immunology, University of Yamanashi Faculty of Medicine
    • Hara Mutsuko
    • Atopy Research Center, Juntendo University School of Medicine
    • Ogawa Hideoki
    • Atopy Research Center, Juntendo University School of Medicine
    • Okumura Ko
    • Atopy Research Center, Juntendo University School of Medicine
    • Shibata Shigenobu
    • Department of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University
    • Nakao Atsuhito
    • Department of Immunology, University of Yamanashi Faculty of Medicine

Abstract

<p><i>Background:</i> Interleukin-33 (IL-33) is an alarmin cytokine that binds to the interleukin 1 receptor-like 1 protein ST2. <i>Clock</i> is a key circadian gene that is essential for endogenous clockworks in mammals. This study investigated whether <i>Clock</i> temporally regulated IL-33-mediated responses in mast cells.</p><p><i>Methods:</i> The kinetics of IL-33-mediated IL-6, IL-13, and TNF-α productions were compared between bone marrow-derived mast cells (BMMCs) from wild-type and <i>Clock</i>-mutated mice (<i>Clock</i><sup><i>Δ19/Δ19</i></sup> mice). The kinetics of the neutrophil influx into the peritoneal cavity or expression of IL-13 and Gob-5 in the lung in response to IL-33 were compared between wild-type and <i>Clock</i><sup><i>Δ19/Δ19</i></sup> mice. We also examined the kinetics of ST2 expression in mast cells and its association with <i>Clock</i> expression.</p><p><i>Results:</i> There was a time-of-day-dependent variation in IL-33-mediated IL-6, IL-13, and TNF-α production in wild-type BMMCs, which was absent in <i>Clock</i>-mutated BMMCs. IL-33-induced neutrophil infiltration into the peritoneal cavity also showed a time-of-day-dependent variation in wild-type mice, which was absent in <i>Clock</i><sup><i>Δ19/Δ19</i></sup> mice. Furthermore, IL-33-induced IL-13 and Gob-5 expression in the lung exhibited a time-of-day-dependent variation in wild-type mice. These temporal variations in IL-33-mediated mast cell responses were associated with temporal variations of ST2 expression in mast cells. In addition, CLOCK bound to the promoter region of ST2 and <i>Clock</i> deletion resulted in down-regulation of ST2 expression in mast cells.</p><p><i>Conclusions:</i> CLOCK temporally gates mast cell responses to IL-33 via regulation of ST2 expression. Our findings provide novel insights into IL-33/mast cell-associated physiology and pathologies.</p>

Journal

  • Allergology International

    Allergology International 66(3), 472-478, 2017

    Japanese Society of Allergology

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