A team led by Anders Blomqvist investigated the role of microsomal prostaglandin E synthase-1 (mPGES-1) — which catalyses the second step in PGE2 production — in the febrile response, by knocking out its expression in mice. Mutant mice were indistinguishable from their wild-type littermates under normal physiological conditions. However, differences emerged following immune challenge with bacterial cell-wall lipopolysaccharide (LPS). Shortly after injection of LPS, the core body temperature of wild-type mice increased significantly and remained elevated for about six hours. By contrast, the temperature of immune-challenged mPGES-1-deficient mice did not differ from that of saline-injected controls. Direct injection of PGE2 into the brains of mutants elicited a robust febrile response, confirming that these mPGES-1-deficient mice retained the capacity to respond to the product of mPGES-1 activity.
Levels of PGE2 in cerebrospinal fluid after administration of LPS mimicked the temperature pattern, increasing in wild-type subjects and remaining static in their mutant counterparts. Incubation of brain homogenates from immune-challenged mice with PGH2, the substrate of mPGES-1, showed that these responses were correlated with enzymatic activity, or lack thereof, in the microsomal fraction. Reverse transcription-polymerase chain reaction was used to confirm that the physiological effects of LPS injection were due to differential expression of mPGES-1 in brain homogenates of wild-type and mutant mice.
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