Prostaglandin D2 produced by hematopoietic prostaglandin D synthase contributes to LPS-induced fever
A large body of evidence has implicated prostaglandin E2 (PGE2) in fever production. However, the role of PGD2 in this context is only poorly understood. We therefore determined by LC-MS/MS analyses the content of PGD2 and PGE2 in cerebrospinal fluid (CSF), plasma and lungs of rats over 5 hours after fever induction by intraperitoneal injection of lipopolysaccharide (LPS, 50 µg/kg). Both PGD2 and PGE2 were detected in CSF, plasma and lungs of saline-treated control animals. The injection of LPS evoked fever and an increase of PGE2 in the CSF, while the CSF content of PGD2 was not significantly altered. However, both PGE2 and PGD2 levels were elevated in plasma and lungs after LPS injection. Interestingly, pretreatment with a novel selective inhibitor of hematopoietic prostaglandin D synthase (H-PGDS), EDJ300520 (10-40 mg/kg p.o.), selectively and dose-dependently prevented the LPS-induced increase of PGD2 in plasma and lungs but did not affect the PGE2 content. Most remarkably, EDJ300520 pretreatment led to an hypothermic response after LPS injection during the first 3 h and prevented fever induction. These data indicate that PGD2 produced peripherally by H-PGDS essentially contributes to LPS-induced fever.