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

Allergol Int. 2017 Jul;66(3):472-478. doi: 10.1016/j.alit.2017.02.004. Epub 2017 Mar 2.


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.

Keywords: CLOCK; Cytokine; IL-33; Mast cells; ST2.

MeSH terms

  • Animals
  • Basophils / drug effects
  • Basophils / immunology
  • Basophils / metabolism
  • CLOCK Proteins / genetics*
  • CLOCK Proteins / metabolism*
  • Cytokines / metabolism
  • Gene Expression Regulation
  • Interleukin-1 Receptor-Like 1 Protein / genetics
  • Interleukin-1 Receptor-Like 1 Protein / metabolism*
  • Interleukin-33 / metabolism*
  • Interleukin-33 / pharmacology
  • Male
  • Mast Cells / drug effects
  • Mast Cells / immunology*
  • Mast Cells / metabolism*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Photoperiod


  • Cytokines
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • CLOCK Proteins