Kawauchi Takahiro, Ishimaru Kayoko, Nakamura Yuki, Nakano Nobuhiro, Hara Mutsuko, Ogawa Hideoki, Okumura Ko, Shibata Shigenobu, Nakao Atsuhito
Department of Immunology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan.
Allergol Int. 2017 Jul;66(3):472-478. doi: 10.1016/j.alit.2017.02.004. Epub 2017 Mar 2.
Interleukin-33 (IL-33) is an alarmin cytokine that binds to the interleukin 1 receptor-like 1 protein ST2. Clock is a key circadian gene that is essential for endogenous clockworks in mammals. This study investigated whether Clock temporally regulated IL-33-mediated responses in mast cells.
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 Clock-mutated mice (Clock 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 Clock mice. We also examined the kinetics of ST2 expression in mast cells and its association with Clock expression.
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 Clock-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 Clock 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 Clock deletion resulted in down-regulation of ST2 expression in mast cells.
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.
白细胞介素-33（IL-33）是一种警报素细胞因子，可与白细胞介素1受体样1蛋白ST2结合。Clock是一个关键的昼夜节律基因，对哺乳动物的内源性生物钟至关重要。本研究调查了Clock是否在时间上调节肥大细胞中IL-33介导的反应。
比较野生型和Clock突变小鼠（Clock小鼠）骨髓来源的肥大细胞（BMMCs）中IL-33介导的IL-6、IL-13和TNF-α产生的动力学。比较野生型和Clock小鼠中IL-33刺激后中性粒细胞流入腹腔的动力学或肺中IL-13和Gob-5的表达。我们还研究了肥大细胞中ST2表达的动力学及其与Clock表达的关系。
野生型BMMCs中IL-33介导的IL-6、IL-13和TNF-α产生存在日变化，而Clock突变的BMMCs中不存在这种变化。IL-33诱导的中性粒细胞向腹腔的浸润在野生型小鼠中也表现出日变化，而Clock小鼠中不存在这种变化。此外，IL-33诱导的肺中IL-13和Gob-5表达在野生型小鼠中呈现日变化。IL-33介导的肥大细胞反应的这些时间变化与肥大细胞中ST2表达的时间变化相关。此外，CLOCK与ST2的启动子区域结合，Clock缺失导致肥大细胞中ST2表达下调。
CLOCK通过调节ST2表达在时间上控制肥大细胞对IL-33的反应。我们的发现为IL-33/肥大细胞相关的生理学和病理学提供了新的见解。
