Prostaglandin D2 regulates Escherichia coli-induced inflammatory responses through TLR2, TLR4, and NLRP3 in macrophages

Prostaglandin D₂ (PGD₂) synthesis is closely associated with the innate immune response mediated by pattern recognition receptors (PPRs). We determined PGD₂ synthesis whether mediated by Toll-like receptor 2 (TLR2), TLR4 and Nod-like receptor pyrin domain-containing protein 3 (NLRP3) in Escherichia coli (E. coli)-, lipopolysaccharide (LPS)- and Braun lipoprotein (BLP)-stimulated macrophages. Our data demonstrate that TLR2, TLR4, and NLRP3 could regulate the synthesis of PGD₂ through cyclo-oxygenase-2 (COX-2) and hematopoietic PGD synthase (H-PGDS) in E. coli-, LPS- or BLP-stimulated macrophages, suggesting that TLR2, TLR4, and NLRP3 are critical in regulating PGD₂ secretion by controlling PGD₂ synthetase expression in E. coli-, LPS- or BLP-stimulated macrophages. The H-PGDS (a PGD₂ specific synthase) inhibitor pre-treatment could down-regulate the secretion of TNF-α, RANTES and IL-10 in LPS- and E. coli-stimulated macrophage. Meanwhile, H-PGDS inhibitor could down-regulate the secretion of TNF-α, while up-regulated RANTES and IL-10 secretion in BLP-stimulated macrophages, suggesting that PGD₂ could regulate the secretion of cytokines and chemokines in E. coli-, LPS- or BLP-stimulated macrophages. Furthermore, exogenous PGD₂ regulates the secretion of cytokines and chemokines through activation of MAPK and NF-κB signaling pathways after E. coli-, LPS- or BLP stimulation in macrophages. Taken together, PGD₂ is found able to regulate E. coli-induced inflammatory responses through TLR2, TLR4, and NLRP3 in macrophages.