Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3

Abstract

Fever, a hallmark of disease, is elicited by exogenous pyrogens, that is, cellular components, such as lipopolysaccharide (LPS), of infectious organisms, as well as by non-infectious inflammatory insults. Both stimulate the production of cytokines, such as interleukin (IL)-1beta, that act on the brain as endogenous pyrogens. Fever can be suppressed by aspirin-like anti-inflammatory drugs. As these drugs share the ability to inhibit prostaglandin biosynthesis, it is thought that a prostaglandin is important in fever generation. Prostaglandin E2 (PGE2) may be a neural mediator of fever, but this has been much debated. PGE2 acts by interacting with four subtypes of PGE receptor, the EP1, EP2, EP3 and EP4 receptors. Here we generate mice lacking each of these receptors by homologous recombination. Only mice lacking the EP3 receptor fail to show a febrile response to PGE2 and to either IL-1beta or LPS. Our results establish that PGE2 mediates fever generation in response to both exogenous and endogenous pyrogens by acting at the EP3 receptor.

EP1‐ and FP‐mediated cross‐desensitization of the alpha (α) and beta (β) isoforms of the human thromboxane A2 receptor

“…While EP 1 , FP and TP receptors are each broadly classified as members of the contractile subgroup of prostanoid receptors , functionally they are primarily associated with distinct physiologic processes and each exhibit distinct patterns of expression Sugimoto et al, 2000). Consistent with the latter, mice deficient in each of these receptors display unique characteristic phenotypes including a reduction in carcinogen-induced colorectal cancer in EP 1 -deficient mice (Ushikubi et al, 1998;Watanabe et al, 1999;Sugimoto et al, 2000), loss of parturition affecting both ovulation and fertilization in FPdeficient mice Hizaki et al, 1999;Kennedy et al, 1999) and increased bleeding tendency associated with TP-deficient mice (Thomas et al, 1998). While EP 1 , FP and TP receptors are also abundantly expressed in the kidney (Sugimoto et al, 2000) and they are each reported to mediate efficient contraction of renal vascular SM and mesangial cells through Ca 2 þ -dependent mechanisms (Mene et al, 1989), their role in renal function as garnered from mouse knockout studies remains to be clearly established.…”

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

“…PTGER3 encodes EP3, one of four receptors for prostaglandin E2, which has many biological functions, including inhibition of gastric acid secretion, inhibition of sodium and water reabsorption in kidney, uterine contractions, fever in response to exogenous and endogenous stimuli, and modulation of neurotransmitter release in central and peripheral neurons. 40 Mice lacking Ep3 have a mild, complex phenotype, including an impaired febrile response, 41 an impaired response of adrenocorticotropic hormone to bacterial endotoxin, 42 exaggerated allergic inflammation, 43 obesity, increased motor activity 44 and increased survival to bacterial infection. 45 PTGER3 is expressed as at least nine multiple splicing variants that have identical ligand binding properties but interact with different second messengers.…”

Behavioral fever in ectothermic vertebrates

“…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). Four subtypes of PGE 2 receptors have been described, namely EP1-EP4 (Oka, 2004), among which EP3 was shown to be critical in the induction of fever (Lazarus et al, 2007;Saper et al, 2012;Ushikubi et al, 1998). These EP3 receptor-bearing neurons are GABAergic neurons (Nakamura et al, 2002), which through neuronal projections inhibit the activity of neurons in dorsomedial nucleus of the hypothalamus (DMH) and rostral medullary raphe (rMR) (Nakamura, 2011).…”