A negative regulator of delayed prostaglandin D2 production in mouse mast cells.
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.
Ueno
Noriko
N
The Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan.
Taketomi
Yoshitaka
Y
Koga
Kumiko
K
Atsumi
Yohei
Y
Kikuchi-Yanoshita
Rei
R
Kudo
Ichiro
I
Murakami
Makoto
M
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*
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