title: Clock-dependent temporal regulation of IL-33/ST2-mediated mast cell response.
abstract: 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/Δ19mice). 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/Δ19mice. 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/Δ19mice. 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.
authors.affiliation: Department of Immunology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kawauchi
authors.affiliation: Department of Immunology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Ishimaru
authors.affiliation: Department of Immunology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nakano
authors.affiliation: Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Hara
authors.affiliation: Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.affiliation: Department of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Department of Immunology, University of Yamanashi Faculty of Medicine, Yamanashi, Japan; Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan. Electronic address: anakao@yamanashi.ac.jp.
authors.forename: Atsuhito
authors.initials: A
authors.lastname: Nakao
mesh_terms: D000818:Animals; D001491:Basophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D056926:CLOCK Proteins / Q000235:genetics* / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000235:genetics / Q000378:metabolism*; D000067596:Interleukin-33 / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017440:Photoperiod
chemical_list: D016207:Cytokines; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D056926:CLOCK Proteins
keywords: CLOCK; Cytokine; IL-33; Mast cells; ST2