Prostaglandin E2 as a mediator of fever: synthesis and catabolism

Abstract

Prostaglandin (PG) E2 is a principal downstream mediator of fever. It is synthesized in three steps catalyzed by phospholipase (PL) A2, cyclooxygenase (COX), and terminal PGE synthase (PGES), where each catalytic activity is represented by multiple enzymes and/or isoenzymes. Inactivation of PGE2 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 PGE2-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 PLA2, 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 PGE2-synthesizing enzymes [secretory (s) PLA2-IIA, cytosolic (c) PLA2-alpha, COX-2, and microsomal (m) PGES-1] and down-regulation of all PGE2 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 PGE2 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 sPLA2-IIA -->COX-2 -->mPGES-1 throughout the body. Phase 3 involves induction of cPLA2-alpha in the hypothalamus and further up-regulation of sPLA2-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 PGE2-dependent inflammatory responses at later stages. Of importance is also that LPS fever is accompanied by transcriptional down-regulation of PGE2 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 PGE2 inactivation is a largely unrecognized mechanism of systemic inflammation. By increasing the blood-brain gradient of PGE2, this mechanism likely facilitates penetration of PGE2 into the brain. The high magnitude of up-regulation of mPGES and sPLA2-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.

Behavioral fever in ectothermic vertebrates

“…The role of PGE 2 in induction of fever in mammals was already reported in 1971 by Milton and Wendlandt (1971) who demonstrated that microinjection of PGE 2 into the third ventricle of conscious cats and rabbits cause a rise of body temperature. The subsequent studies using inhibitors of PGE 2 synthesis clearly confirmed that PGE 2 plays essential role in fever expressed by mammals (reviewed by Ivanov and Romanovsky, 2004;Blatteis et al, 2005). PGE 2 biosynthesis involves three successive enzymatic reactions (Pecchi et al, 2009): firstly, arachidonic acid (AA) is released by the action of phospholipase A2 (PLA2) on the cell membrane phospholipids; secondly, AA is metabolized in PGG 2 then converted to PGH 2 by the action of COX; thirdly, PGH 2 is finally metabolized in PGE 2 by the mPGES1.…”

“…In addition to the PGE 2 locally produced in the brain, PGE 2 can also be secreted at the periphery predominantly by hepatic and pulmonary macrophages (Li et al, 2006;Simm et al, 2016;Steiner et al, 2006). This peripheral PGE 2 binds to albumin which protects it from enzymatic degradation during its journey to the brain via the bloodstream (Ivanov and Romanovsky, 2004). Independently of its peripheral or cerebral origin, PGE 2 bind to a PGE 2 receptors on a specific group of neurons in the median preoptic nucleus (MnPO).…”

Prostaglandin E2 Inhibits Its Own Renal Transport by Downregulation of Organic Anion Transporters rOAT1 and rOAT3

“…In general, fever-generating PGE 2 is thought to be produced in the brain (16). Nevertheless, it is shown that substantial amounts of peripheral PGE 2 enter hypothalamic structures (17), and recent data support the idea of blood-derived PGE 2 's playing an important role in fever (18,19). The authors showed that in a rat fever model, the main enzymes that lead to generation of PGE 2 are dramatically upregulated in liver and lung (and hypothalamus) (20).…”

Calorie restriction attenuates LPS-induced sickness behavior and shifts hypothalamic signaling pathways to an anti-inflammatory bias

“…mPGES-1 expression profiles were similar to COX-2, which isn't surprising given their direct involvement with each other. mPGES-1, a PGE 2 synthase enzyme, is functionally coupled with COX-2 (58); however, mPGES-1 continues to be expressed once COX-2 has declined (36). Furthermore, mPGES-1 is increased during inflammation and is downregulated by glucocorticoids (35,41).…”