IMR Press / FBL / Volume 9 / Issue 1 / DOI: 10.2741/1301

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Article
Fever in systemic inflammation: roles of purines
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1 Department of Physiology, Royal Free and University College London Medical School, London NW3 2PF, UK
2 Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, UK
3 Institute of Physiology, National Academy of Sciences of Belarus, Minsk 220725, Belarus
Academic Editor:Andrej Romanovsky
Front. Biosci. (Landmark Ed) 2004, 9(1), 1011–1022; https://doi.org/10.2741/1301
Published: 1 January 2004
(This article belongs to the Special Issue Fever and hypothermia in systemic Inflammation)
Abstract

Extracellular purine nucleotide and nucleoside signalling molecules, such as ATP and adenosine, acting through specific receptors (P2 and P1, respectively) play significant roles in the mechanisms underlying the febrile response. A variety of P2 and P1 receptor subunits have been identified in the hypothalamus, the area of the brain that orchestrates the febrile response. Importantly, both ATP and adenosine have been shown to modulate release and/or action of cytokines that are implicated in fever, as well as to be involved in the central mechanisms of cardiovascular and respiratory control. Our data indicate that at the level of the anterior hypothalamus extracellular ATP is involved in the control of the development of fever. A population of warm-sensitive neurones in the anterior hypothalamus is likely to be the site of action of ATP on body temperature. ATP-induced cytokine release does not appear to play a significant role in the hypothalamic mechanisms leading to the development of the febrile response. However, the blockade of fever by P2 receptor antagonists given systemically suggests that ATP-mediated signalling may play a role in the release of pyrogenic cytokines in the periphery. At the level of the anterior hypothalamus adenosine appears to be released tonically, and acts to maintain body temperature under afebrile conditions. There is also evidence that adenosine-mediated signalling may play a role in the hypothalamic mechanisms controlling the degree of body temperature increase during fever. Our investigations have identified possible mechanisms by which purines modulate the febrile response. The actions of purines on body temperature during fever are most likely "site specific" (brain vs. periphery), may or may not involve their effect on cytokine release and/or action, and are likely to involve P2 and P1 receptors of different subtypes. Further extensive studies are needed to elucidate these mechanisms in greater detail and may lead to the development of new approaches for modifying febrile, cytokine and acute-phase responses to infection.

Keywords
Adenosine
adenosine receptor
ATP
body temperature
brainstem
cytokine
febrile response
fever
hypothalamus
inflammation
P2 receptors
P2X
purine
thermoregulation
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