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

Nature volume 395, pages 281–284 (1998)Cite this article

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)-1β, that act on the brain as endogenous pyrogens1. Fever can be suppressed by aspirin-like anti-inflammatory drugs. As these drugs share the ability to inhibit prostaglandin biosynthesis2, it is thought that a prostaglandin is important in fever generation. Prostaglandin E2 (PGE2) may be a neural mediator of fever3, but this has been much debated1,4,5,6,7. PGE2 acts by interacting with four subtypes of PGE receptor, the EP1, EP2, EP3 and EP4 receptors8. 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-1β or LPS. Our results establish that PGE2 mediates fever generation in response to both exogenous and endogenous pyrogens by acting at the EP3 receptor.

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Figure 1: Targeted disruption of the EP1 and EP3 receptor genes.
Figure 2: Effects of PGE2 on body temperature in wild-type and receptor-deficient mice.
Figure 3: Loss of the IL-1β-induced febrile response in EP3-receptor-deficient mice.
Figure 4: Responses to LPS in N4 mice lacking the EP1 or EP3 receptor.

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Acknowledgements

We thank Y. Kataoka and K. Ishikawa for injection of embryonic stem cells, K.Takahashi for animal breeding, and K. Okuyama and T. Arai for secretarial assistance. This work was supported by grants-in-aid from the Ministry of Education, Science, Sports and Culture of Japan and from the Ministry of Health and Welfare of Japan, and by grants from the Uehara Memorial Foundation, the Smoking Research Foundation and the Japanese Foundation on Metabolism and Diseases.

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Author notes

  1. Fumitaka Ushikubi and Eri Segi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, and Department of Physiological Chemistry, Faculty of Medicine, Faculty of Pharmaceutical Sciences, Kyoto University, 606-8315, Kyoto, Japan

    Fumitaka Ushikubi, Takahiko Murata, Toshiyuki Matsuoka, Takuya Kobayashi & Shuh Narumiya

  2. Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University, 606-8315, Kyoto, Japan

    Eri Segi, Yukihiko Sugimoto, Hiroko Hizaki, Kazuhito Tuboi, Masato Katsuyama & Atsushi Ichikawa

  3. Division of Molecular and Cellular Immunology, Research Institute, Osaka Medical Center for Maternal and Child Health, 594-1101, Osaka, Japan

    Takashi Tanaka & Nobuaki Yoshida

Authors
  1. Fumitaka Ushikubi
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  13. Shuh Narumiya
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Corresponding author

Correspondence to Shuh Narumiya.

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Ushikubi, F., Segi, E., Sugimoto, Y. et al. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 395, 281–284 (1998). https://doi.org/10.1038/26233

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