Microsomal PGE synthase-1 is essential to the production of PGE₂ in the brain and fever under inflammtory/infectious states.

Abstract

Prostaglandin E₂ (PGE₂), the final mediator of fever, is thought to be produced in brain endothelial cells through the enzyme cascade of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1), since various pyrogenic stimuli induce these enzymes in brain endothelial cells. The essential role of COX-2 in brain PGE₂ synthesis and fever has been shown by using COX-2-specific inhibitors or COX-2-gene deficient mice. We here examined the role of mPGES-1 in these reactions by using mPGES-1 gene deficient (mPGES-1(-/-)) mice. Abdominal temperature of mPGES-1(-/-) mice and wild type mice were monitored with a telemetry system. The mice were challenged with 4 pyrogenic stimuli, i.e., lipopolysachharide (LPS, intraperitoneal injection), turpentine (subcutaneous injection), interleukin-1 beta (intracerebroventricular injection), and PGE₂ (intracerebroventricular injection). Both types of mice responded to PGE₂ with a similar degree of fever, whereas pyrogenic stimuli other than PGE₂ evoked fever only in wild type mice. The LPS stimuli elevated PGE₂ level in the brain only in wild type mice whereas LPS-induced plasma interleukin-1 beta and brain endothelial COX-2 levels were similar in these two types of mice. These results clearly demonstrate that mPGES-1 plays an essential role in the brain PGE₂ synthesis and fever under various inflammatory/infectious states. [Jpn J Physiol 54 Suppl:S230 (2004)]