Prostaglandin E2 as a mediator of fever:: Synthesis and catabolism

Prostaglandin (PG) E-2 is a principal downstream mediator of fever. It is synthesized in three steps catalyzed by phospholipase (PL) A(2), cyclooxygenase (COX), and terminal PGE synthase (PGES), where each catalytic activity is represented by multiple enzymes and/or isoenzymes. Inactivation of PGE(2) occurs primarily in the lungs and liver via carrier-mediated cellular uptake and enzymatic oxidation. The two principal carriers are PG transporter (PGT) and multispecific organic anion transporter (MOAT); the two principal PGE(2)-inactivating enzymes are 15-hydroxy-PG dehydrogenase (15-PGDH) and carbonyl reductase (CR). Our data [Ivanov A. I. et al. Am J Physiol Regul Integr Comp Physiol 283, R1104-R1117 (2002); ibid. 284, R698-R706 (2003)] are used to analyze the relationship between transcriptional regulation of PLA(2), COX, PGES, PGT, MOAT, 15-PHDH, and CR, on one hand, and the triphasic febrile response of rats to lipopolysaccharide (LPS), on the other. It is concluded that LPS fever is accompanied by up-regulation of four PGE(2)-synthesizing enzymes [secretory (s) PLA(2)-IIA, cytosolic (c) PLA(2)-alpha, COX-2, and microsomal (m) PGES-1] and down-regulation of all PGE(2) carriers and dehydrogenases studied (PGT, MOAT, 15PGDH, and CR). It is further concluded that different febrile phases employ different mechanisms to mount an increase in the PGE(2) level. Phase 1 involves transcriptional up-regulation of the couple COX-2 --> mPGES-1 in the liver and lungs. Phase 2 entails robust up-regulation of the major inflammatory triad sPLA(2)-IIA --> COX-2 --> mPGES-1 throughout the body. Phase 3 involves induction of cPLA(2)-alpha in the hypothalamus and further up-regulation of sPLA(2)-IIA and mPGES throughout the body. Importantly, Phase 3 occurs despite a drastic decrease in the expression of COX-1 and -2 in both the brain and periphery, thus suggesting that transcriptional up-regulation of COX-2 is not an obligatory mechanism of PGE(2)-dependent inflammatory responses at later stages. Of importance is also that LPS fever is accompanied by transcriptional down-regulation of PGE(2) transporters and dehydrogenases: 15-PGDH in the lungs at Phase 1; 15-PGDH and CR in the lungs at Phase 2; and PGT, MOAT, 15-PGDH, and CR in the liver and lungs at Phase 3. The transcriptional down-regulation of proteins involved in PGE(2) inactivation is a largely unrecognized mechanism of systemic inflammation. By increasing the blood-brain gradient of PGE(2), this mechanism likely facilitates penetration of PGE(2) into the brain. The high magnitude of up-regulation of mPGES and sPLA(2)-IIA (1,260 and 130 fold, respectively) and that of down-regulation of 15-PGES (30 fold) during LPS fever makes these enzymes attractive targets for anti-inflammatory therapy.