Heat relief

Inflammatory molecules called prostaglandins (PGs) facilitate induction of the febrile response to infection. Fever-alleviating drugs, such as ibuprofen, are used by millions of people every day, and act by inhibiting cyclooxygenase (COX), which catalyses the first step in the formation of PGs from arachidonic acid. But the use of COX inhibitors is associated with severe side effects, such as gastric intolerance and depression of blood clotting, which are probably related to their non-specific effects on the synthesis of several PGs. Targeting PGs that are specifically involved in eliciting fever might permit the development of antipyretic drugs with an improved safety profile. A study published recently in Nature Neuroscience brings us one step closer to realizing this goal.

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.

Interestingly, expression of another PG-synthesizing enzyme — mPGES-2 — was not upregulated by immune challenge in wild-type mice, indicating that mPGES-1 is specifically involved in facilitating fever. Similarly, the response of COX-2 to LPS injection was not affected by the mPGES-1 mutation, being upregulated in both mutant and wild-type mice. These results show that, unlike present-generation COX inhibitors, compounds that target mPGES-1 should specifically inhibit the synthesis of fever-inducing PGE₂, without affecting the production of other PGs. Side effects of antipyretic drugs might thereby become a thing of the past.