title: A negative regulator of delayed prostaglandin D2 production in mouse mast cells.
abstract: We have previously shown that maturation of mouse bone marrow-derived mast cells (BMMCs) into connective tissue mast cells (CTMCs) upon coculture with fibroblasts in the presence of stem cell factor (kit ligand) is accompanied by marked induction of a panel of genes, one of which was identified as NLRP3. Here we report that NLRP3 acts as a novel negative regulator of delayed prostaglandin (PG) D(2) production in BMMCs. We found that, apart from its cell maturation-associated induction, NLRP3 expression was markedly induced in BMMCs several hours after FcepsilonRI crosslinking or cytokine stimulation. Ectopic expression of NLRP3 in BMMCs resulted in marked attenuation of cyclooxygenase (COX)-2-dependent delayed PGD(2) generation, whereas it had no effects on other effector functions, including degranulation, COX-1-dependent immediate PGD(2) generation and cytokine/chemokine expression. The suppression of delayed PGD(2) generation by NLRP3 was preceded by a transient decrease of NF-kappaB activation and a marked reduction in the expression of COX-2, but not that of cytosolic phospholipase A(2) alpha (cPLA(2)alpha), COX-1 and hematopoietic PGD(2) synthase. Moreover, in CTMC-like differentiated cells in which endogenous NLRP3 expression was induced, cytokine-stimulated induction of COX-2 and attendant delayed PGD(2) generation were markedly reduced. Our results suggest that, in mouse mast cells, NLRP3 counter-regulates COX-2-dependent sustained production of PGD(2), a prostanoid that exhibits both pro- and anti-allergic effects, thereby potentially influencing the duration of allergic and other mast cell-associated inflammatory diseases.
authors.affiliation: The Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Ueno
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Taketomi
authors.forename: Kumiko
authors.initials: K
authors.lastname: Koga
authors.forename: Yohei
authors.initials: Y
authors.lastname: Atsumi
authors.forename: Rei
authors.initials: R
authors.lastname: Kikuchi-Yanoshita
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kudo
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D008407:Mast Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015230:Prostaglandin D2 / Q000096:biosynthesis*
chemical_list: D002352:Carrier Proteins; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D015230:Prostaglandin D2