Prostaglandin E2 as a fever mediator: A further look

Blatteis, Clark M.; Sehic, Elmir; Hunter, W. H.

doi:10.1016/0928-4680(94)90223-2

Cited by 27 publications

(43 citation statements)

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“…Electrical stimulation of the ascending noradrenergic system in the brain stem yields the same result (67), whereas chemical sympathectomy abrogates this response (66). PGE 2 microinjected into the POA also is thermogenic (5). NE is quickly degraded and removed from the brain whereas PGE 2 is removed much more slowly (74), so that the action of the latter may outlast the effect of the former.…”

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confidence: 74%

“…Thus it is well documented that peripheral pyrogens activate noradrenergic pathways in the brain (14,26) and that NE is released in the POA in conjunction with the febrile response (31,38). The involvement of PGE 2 in fever production is now all but axiomatic, but the dynamics and source of the pyrogeninduced elevation of preoptic PGE 2 levels are still controversial (5). If NE were the direct stimulus for its increased production, it might be expected from the preceding that it would begin promptly and that, in turn, the elevated PGE 2 levels would inhibit the further release of NE.…”

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Preoptic α₁- and α₂-noradrenergic agonists induce, respectively, PGE₂-independent and PGE₂-dependent hyperthermic responses in guinea pigs

Feleder¹,

Perlik²,

Blatteis³

2004

American Journal of Physiology-Regulatory, Integrative and Comp

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Feleder, Carlos, Vit Perlik, and Clark M. Blatteis. Preoptic ␣1-and ␣2-noradrenergic agonists induce, respectively, PGE2-independent and PGE2-dependent hyperthermic responses in guinea pigs. Am J Physiol Regul Integr Comp Physiol 286: R1156 -R1166, 2004. First published February 12, 2004 10.1152/ajpregu.00486.2003We have shown previously that norepinephrine (NE) microdialyzed into the preoptic area (POA) of conscious guinea pigs stimulates local PGE2 release. To identify the cyclooxygenase (COX) isozyme that catalyzes the production of this PGE2 and the adrenoceptor (AR) subtype that mediates this effect, we microdialyzed for 6 h NE, cirazoline (␣1-AR agonist), and clonidine (␣2-AR agonist) into the POA of conscious guinea pigs pretreated intrapreoptically (intra-POA) with SC-560 (COX-1 inhibitor) or nimesulide or MK-0663 (COX-2 inhibitors) and measured the animals' core temperature (Tc) and intra-POA PGE2 responses. Cirazoline induced Tc rises promptly after the onset of its dialysis without altering PGE2 levels. NE and clonidine caused early falls followed by late rises of Tc; intra-POA PGE2 levels were closely correlated with this thermal course. COX-1 inhibition attenuated the clonidine-induced Tc and PGE2 falls but not the NE-elicited hyperthermia, but COX-2 inhibition suppressed both the clonidine-and NE-induced Tc and PGE2 rises. Coinfused cirazoline and clonidine reproduced the late Tc rise of clonidine but not its early fall and also not the early rise produced by cirazoline; on the other hand, the PGE2 responses were similar to those to NE. Prazosin (␣1-AR antagonist) and yohimbine (␣2-AR antagonist) blocked the effects of their respective agonists. These results indicate that ␣1-and ␣ 2-AR agonists microdialyzed into the POA of conscious guinea pigs evoke distinct Tc responses: ␣1-AR activation produces quick, PGE2-independent T c rises, and ␣2-AR stimulation causes an early Tc fall and a late, COX-2/PGE2-dependent Tc rise. thermoregulation; cyclooxygenase inhibitors; prostaglandin E 2; noradrenergic agonists and antagonists; care temperature; norepinephrine THERE IS MUCH EVIDENCE that norepinephrine (NE) and prostaglandin (PG) E 2 interact in many tissues, including nervous tissue (33). For example, an intimate association between NE and PGE 2 is well documented in the peripheral nervous system (21); to wit, the stimulation of sympathetic neurons induces the postsynaptic release of PGE 2 , which then limits the further presynaptic release of NE, thereby modulating the activity of noradrenergic neurons. It is also well documented that NE induces PGE 2 synthesis in brain tissue (23, 60) where its feedback inhibition of the presynaptic release of NE has been similarly documented (3,13,54).In conscious guinea pigs, NE microinjected into the preoptic-anterior hypothalamic area [POA, the locus of the thermal controller (7)] evokes body (core) temperature (T c ) rises (75,47). Electrical stimulation of the ascending noradrenergic system in the brain stem yields the same result (67), whereas chemical sympat...

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Preoptic α₁- and α₂-noradrenergic agonists induce, respectively, PGE₂-independent and PGE₂-dependent hyperthermic responses in guinea pigs

Feleder¹,

Perlik²,

Blatteis³

2004

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Within 1 h of arousal from hibernation, however, LPS-treated squirrels exhibited a fever of 1-1.5°C, which was sustained for Ͼ8 h. The inability of LPS to induce fever while One or more of the cellular and humoral signaling events involved in the APR may be interdicted in hibernating squirrels. In normothermic mammals, LPS treatment induces fever by triggering secretion of cytokines and other humoral mediators from macrophages and monocytes at the site of infection (3,38). The cytokines IL-1␤, IL-6, and tumor necrosis factor-␣ mimic, to varying degrees, LPS-induced fever in mice, rats, and rabbits; inhibition of these cytokines attenuates LPS-induced fevers (38).…”

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confidence: 99%

Periodic arousal from hibernation is necessary for initiation of immune responses in ground squirrels

Prendergast

Freeman²,

Zucker

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

203

187

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Golden-mantled ground squirrels (Spermophilus lateralis) undergo seasonal hibernation during which core body temperature (Tb) values are maintained 1-2°C above ambient temperature. Hibernation is not continuous. Squirrels arouse at ϳ7-day intervals, during which Tb increases to 37°C for ϳ16 h; thereafter, they return to hibernation and sustain low Tbs until the next arousal. Over the course of the hibernation season, arousals consume 60-80% of a squirrel's winter energy budget, but their functional significance is unknown and disputed. Host-defense mechanisms appear to be downregulated during the hibernation season and preclude normal immune responses. These experiments assessed immune function during hibernation and subsequent periodic arousals. The acute-phase response to bacterial lipopolysaccharide (LPS) was arrested during hibernation and fully restored on arousal to normothermia. LPS injection (ip) resulted in a 1-1.5°C fever in normothermic animals that was sustained for Ͼ8 h. LPS was without effect in hibernating squirrels, neither inducing fever nor provoking arousal, but a fever did develop several days later, when squirrels next aroused from hibernation; the duration of this arousal was increased sixfold above baseline values. Intracerebroventricular infusions of prostaglandin E2 provoked arousal from hibernation and induced fever, suggesting that neural signaling pathways that mediate febrile responses are functional during hibernation. Periodic arousals may activate a dormant immune system, which can then combat pathogens that may have been introduced immediately before or during hibernation. circannual rhythms; Spermophilus lateralis; neural-immune interactions MAINTENANCE OF IMMUNE FUNCTION requires considerable energy expenditure (42, 62) and may limit or constrain the extent to which animals engage in other energetically demanding activities (39,40,58). Large seasonal increases in energy expenditure associated with reproduction or low ambient temperatures (5) may compete with the day-to-day demands of host defense. Sustained regulated hypothermia, in the form of hibernation or daily torpor, has been adopted by some mammals to contend with seasonal changes in temperature and energy availability. Golden-mantled ground squirrels (Spermophilus lateralis) spend 5-6 mo each year in deep hibernation, during which core body temperature (T b ) is maintained at 1-2°C above ambient temperature (T a ). Many physiological systems, including brain and renal metabolism, respiration, cardiac function, digestion, and mitosis, are arrested or substantially reduced during a hibernation bout (12,29,31,51,54,70,74).Although immune function during hibernation has been little studied, robust cell-mediated and humoral immune responses to pathogens are thought to be compromised. Impaired immune function in hibernators has been inferred from in vitro splenocyte proliferation or reduced antibody production over the course of an entire hibernation season (4,7,15,32,46,48,60). We are unaware of any studies that have assesse...

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“…Fever is mediated by prostaglandin (PG) E 2 (8). Indeed, pharmacological blockade (42,58) or genetic abrogation (30,43,65) of PG synthesis or PGE receptors attenuates this response.…”

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“…Fever-associated production of PGE 2 occurs via transcriptional upregulation of several enzymes within the PGE 2 -synthesizing cascade, most markedly secretory phospholipase A 2 group IIA, cyclooxygenase (COX)-2, and microsomal PGE synthase (17,26,34,68). Pyrogenic PGE 2 is generally thought to be produced in the hypothalamus, the brain's "febrigenic center" (8). Yet, a contribution of peripherally originated PGE 2 to the febrile response has also been proposed (12) and confirmed by several lines of studies (13,16,47).…”

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Expression of genes controlling transport and catabolism of prostaglandin E₂in lipopolysaccharide fever

Ivanov¹,

Scheck

Romanovsky³

2003

American Journal of Physiology-Regulatory, Integrative and Comp

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) E2 is a principal downstream mediator of fever and other symptoms of systemic inflammation. Its inactivation occurs in peripheral tissues, primarily the lungs and liver, via carrier-mediated cellular uptake and enzymatic oxidation. We hypothesized that inactivation of PGE2 is suppressed during LPS fever and that transcriptional downregulation of PGE2 carriers and catabolizing enzymes contributes to this suppression. Fever was induced in inbred Wistar-Kyoto rats by intravenous LPS (50 g/kg); the controls received saline. Samples of the liver, lungs, and hypothalamus were harvested 0, 0.5, 1.5, and 5 h postinjection. The expression of the two principal transmembrane PGE2 carriers (PG transporter and multispecific organic anion transporter) and the two key PGE2-inactivating enzymes [15-hydroxy-PG dehydrogenase (15-PGDH) and carbonyl reductase] was quantified by RT-PCR. All four genes of interest were downregulated in peripheral tissues (but not the brain) during fever. Most remarkably, the expression of hepatic 15-PGDH was decreased 26-fold 5 h post-LPS, whereas expression of pulmonary 15-PGDH was downregulated (as much as 18-fold) throughout the entire febrile course. The transcriptional downregulation of several proteins involved in PGE2 inactivation, first reported here, is an unrecognized mechanism of systemic inflammation. By increasing the bloodbrain gradient of PGE2, this mechanism likely facilitates penetration of PGE2 into the brain and prevents its elimination from the brain. systemic inflammation; multispecific organic anion transporter; prostaglandin transporter; 15-hydroxyprostaglandin dehydrogenase; carbonyl reductase ON A SYSTEMIC INFLAMMATORY challenge (e.g., with bacte-

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Prostaglandin E2 as a fever mediator: A further look

Cited by 27 publications

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Preoptic α₁- and α₂-noradrenergic agonists induce, respectively, PGE₂-independent and PGE₂-dependent hyperthermic responses in guinea pigs

Preoptic α₁- and α₂-noradrenergic agonists induce, respectively, PGE₂-independent and PGE₂-dependent hyperthermic responses in guinea pigs

Periodic arousal from hibernation is necessary for initiation of immune responses in ground squirrels

Expression of genes controlling transport and catabolism of prostaglandin E₂in lipopolysaccharide fever

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Prostaglandin E2 as a fever mediator: A further look

Cited by 27 publications

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Preoptic α1- and α2-noradrenergic agonists induce, respectively, PGE2-independent and PGE2-dependent hyperthermic responses in guinea pigs

Preoptic α1- and α2-noradrenergic agonists induce, respectively, PGE2-independent and PGE2-dependent hyperthermic responses in guinea pigs

Periodic arousal from hibernation is necessary for initiation of immune responses in ground squirrels

Expression of genes controlling transport and catabolism of prostaglandin E2in lipopolysaccharide fever

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Preoptic α₁- and α₂-noradrenergic agonists induce, respectively, PGE₂-independent and PGE₂-dependent hyperthermic responses in guinea pigs

Preoptic α₁- and α₂-noradrenergic agonists induce, respectively, PGE₂-independent and PGE₂-dependent hyperthermic responses in guinea pigs

Expression of genes controlling transport and catabolism of prostaglandin E₂in lipopolysaccharide fever