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

  title={Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3},
  author={Fumitaka Ushikubi and Eri Segi and Yukihiko Sugimoto and Takahiko Murata and Toshiyuki Matsuoka and Takuya Kobayashi and Hiroko Hizaki and Kazuhito Tuboi and Masato Katsuyama and Atsushi Ichikawa and Takashi Tanaka and Nobuaki Yoshida and Shuh Narumiya},
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)-1β, 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… 

Deletion of Prostaglandin E2 Synthesizing Enzymes in Brain Endothelial Cells Attenuates Inflammatory Fever

It is demonstrated that PGE2 synthesis in brain endothelial cells is critical for inflammation-induced fever, and mice with selective deletion of COX-2 and mPGES1 shown strongly attenuated febrile responses to peripheral immune challenge.

Impaired febrile responses to immune challenge in mice deficient in microsomal prostaglandin E synthase-1.

It is indicated that central PGE2 synthesis by mPGES-1 is a general and critical mechanism for fever during infectious and inflammatory conditions that is distinct from the mechanism(s) underlying the circadian temperature regulation and stress-induced hyperthermia, as well as the inflammation-induced activity depression.

Impaired adrenocorticotropic hormone response to bacterial endotoxin in mice deficient in prostaglandin E receptor EP1 and EP3 subtypes

It is suggested that EP1- and EP3-mediated neuronal pathways converge at corticotropin-releasing hormone-containing neurons in the PVN to induce HPA axis activation upon sickness.

The differential role of prostaglandin E2 receptors EP3 and EP4 in regulation of fever.

  • M. Lazarus
  • Biology
    Molecular nutrition & food research
  • 2006
A fever model is discussed in which the preoptic area contains the mechanisms for both hyperthermic and hypothermic responses and EP receptors in the median pre optic area (MnPO) modulate the thermogenic system.

Neural Mechanisms of Inflammation-Induced Fever

  • A. BlomqvistD. Engblom
  • Biology, Medicine
    The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
  • 2018
It is concluded that there is unequivocal evidence for a humoral signaling pathway by which proinflammatory cytokines, through their binding to receptors on brain endothelial cells, evoke fever by eliciting prostaglandin E2 synthesis in these cells.

Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase

Prostaglandin (PG)E2 is a potent mediator of pain and inflammation, and high levels of this lipid mediator are observed in numerous disease states. The inhibition of PGE2 production to control pain

E-Prostanoid 3 Receptor Deletion Improves Pulmonary Host Defense and Protects Mice from Death in Severe Streptococcus pneumoniae Infection1

In infected wild-type and EP3+/+ mice with the important respiratory pathogen Streptococcus pneumoniae or injected mice i.p. with LPS, it is observed that EP3−/− mice were protected from mortality after infection or LPS and underscore the complex nature of PGE2 immunomodulation in the context of host-microbial interactions in the lung.

Fever During Localized Inflammation in Mice Is Elicited by a Humoral Pathway and Depends on Brain Endothelial Interleukin-1 and Interleukin-6 Signaling and Central EP3 Receptors

Fever during localized inflammation is not mediated by neural signaling from the inflamed site, as previously suggested, but is dependent on humoral signaling that involves interleukin actions on brain endothelial cells, probably facilitating PGE2 entry into the brain from the circulation and hence representing a mechanism distinct from that at work during systemic inflammation.

[Pain, fever and prostanoids].

Results indicate that PGE2 works as a common final mediator of the febrile response and that this action is mediated by the EP3 receptor, and the determination of precise roles of prostanoids in pain and fever may provide novel targets for antipyretic analgesics with fewer side effects.

Central mediators involved in the febrile response: effects of antipyretic drugs

It is shown that some endogenous mediators can still induce the febrile response even when known antipyretics reduce the levels of prostaglandins in the central nervous system, and studies suggest that centrally produced mediators other than prostaglands participate in the genesis of fever.



Prostaglandin E as the neural mediator of the febrile response.

Evidence from the literature that supports a role for prostaglandin E as the neural mediator of the febrile response is reviewed and presented, and the conclusion is drawn that the evidence available is more than sufficient to support the initial hypothesis.

Altered pain perception and inflammatory response in mice lacking prostacyclin receptor

It is established that prostacyclin is an antithrombotic agent in vivo and evidence for its role as a mediator of inflammation and pain is provided.

Is prostaglandin E the neural mediator of the febrile response? The case against a proven obligatory role.

It is concluded that PGE may contribute to the neural responses in fever but is not essential, and that antipyretic drugs may act in ways other than inhibiting PGE synthesis.

Fever: Role of Pyrogens and Cryogens

Before any cytokine or hormone can be characterized as an EP or EC (or, for that matter, as being involved in any of the acute phase responses), clearly established rules must be followed, which are patterned after the traditional criteria used by Koch to distinguish a pathogenic microorganism from a benign one.

Interleukin-8 induces fever by a prostaglandin-independent mechanism.

Inhibition of IL-8 by glucocorticoids contributes to the antipyretic effects of these drugs in fevers resistant to cyclooxygenase inhibitors, and dexamethasone markedly attenuated pyrogenic responses toIL-8 and IL-1 beta.

Macrophage inflammatory protein-1: a prostaglandin-independent endogenous pyrogen.

Macrophage inflammatory protein-1 (MIP-1) produced a monophasic fever of rapid onset whose magnitude was equal to or greater than that of fevers produced with either recombinant human cachectin (or

Lipopolysaccharide (LPS)-induced Macrophage Activation and Signal Transduction in the Absence of Src-Family Kinases Hck, Fgr, and Lyn

Direct evidence is provided that three Src-family kinases Hck, Fgr, and Lyn are not obligatory for LPS-initiated signal transduction.

Prostaglandin formation in feline cerebral microvessels: effect of endotoxin and interleukin-1.

It is concluded that the cerebral microvasculature does not lend itself to an active role in the genesis of fever by being the site at which blood-borne interleukin-1 promotes prostaglandin E2 synthesis.

Evidence that brain prostaglandin synthesis is not essential in fever.

In rabbits, fever was produced by the injection of leucocyte pyrogen in a lateral cerebral ventricle and the latency, rate of rise and magnitude of the fever was unaffected by the simultaneous intraventricular injection of two prostaglandin antagonists.