Prostaglandin E2-synthesizing enzymes in fever: differential transcriptional regulation

Abstract
The febrile response to lipopolysaccharide (LPS) consists of three phases ( phases I–III), all requiring de novo synthesis of prostaglandin (PG) E2. The major mechanism for activation of PGE2-synthesizing enzymes is transcriptional upregulation. The triphasic febrile response of Wistar-Kyoto rats to intravenous LPS (50 μg/kg) was studied. Using real-time RT-PCR, the expression of seven PGE2-synthesizing enzymes in the LPS-processing organs (liver and lungs) and the brain “febrigenic center” (hypothalamus) was quantified. Phase I involved transcriptional upregulation of the functionally coupled cyclooxygenase (COX)-2 and microsomal (m) PGE synthase (PGES) in the liver and lungs. Phase II entailed robust upregulation of all enzymes of the major inflammatory pathway, i.e., secretory (s) phospholipase (PL) A2-IIA → COX-2 → mPGES, in both the periphery and brain. Phase III was accompanied by the induction of cytosolic (c) PLA2-α in the hypothalamus, further upregulation of sPLA2-IIA and mPGES in the hypothalamus and liver, and a decrease in the expression of COX-1 and COX-2 in all tissues studied. Neither sPLA2-V nor cPGES was induced by LPS. The high magnitude of upregulation of mPGES and sPLA2-IIA (1,257-fold and 133-fold, respectively) makes these enzymes attractive targets for anti-inflammatory therapy.