Prostaglandin [E.sub.2]-synthesizing enzymes in fever: differential transcriptional regulation

The febrile response to lipopolysaccharide (LPS) consists of three phases (phases I-III), all requiring de novo synthesis of prostaglandin (PG) [E.sub.2]. The major mechanism for activation of PG[E.sub.2]-synthesizing enzymes is transcriptional upregulation. The triphasic febrile response of Wistar-Kyoto rats to intravenous LPS (50 [micro]g/kg) was studied. Using real-time RT-PCR, the expression of seven PG[E.sub.2]-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 H entailed robust upregulation of all enzymes of the major inflammatory pathway, i.e., secretory (s) phospholipase (PL) [A.sub.2]-IIA -> COX-2 -> mPGES, in both the periphery and brain. Phase III was accompanied by the induction of cytosolic (c) PL[A.sub.2-[alpha]] in the hypothalamus, further upregulation of sPL[A.sub.2]-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 sPL[A.sub.2]-V nor cPGES was induced by LPS. The high magnitude of upregulation of mPGES and sPL[A.sub.2]-IIA (1,257-fold and 133-fold, respectively) makes these enzymes attractive targets for anti-inflammatory therapy. cyclooxygenases; phospholipases; terminal prostaglandin E synthases; lipopolysaccharide; febrile phases