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

Takahiro Kawauchi, Kayoko Ishimaru, Yuki Nakamura, Nobuhiro Nakano, Mutsuko Hara, Hideoki Ogawa, Ko Okumura, Shigenobu Shibata, Atsuhito Nakao*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)


Background 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. Methods 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 (ClockΔ19/Δ19 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 ClockΔ19/Δ19 mice. We also examined the kinetics of ST2 expression in mast cells and its association with Clock expression. Results 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 ClockΔ19/Δ19 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. Conclusions 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.

Original languageEnglish
Pages (from-to)472-478
Number of pages7
JournalAllergology International
Issue number3
Publication statusPublished - 2017 Jul
Externally publishedYes


  • Cytokine
  • IL-33
  • Mast cells
  • ST2

ASJC Scopus subject areas

  • Immunology and Allergy


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