It is generally believed that fever is caused not by exogenous, but by endogenous pyrogens, members of an array of peptide mediators called cytokines. These are elaborated and released into the circulation largely by systemic mononuclear phagocytes activated by the exogenous agents, and transported to the preoptic anterior hypothalamic area (POA) of the brain, where they act. Prostaglandin E2 (PGE2) is thought to be a fever mediator in the POA, induced by these cytokines. Although the intrapreoptic level of PGE2 rises rapidly following the intravenous (iv) administration of exogenous (e.g., lipopolysaccharide, LPS) or endogenous pyrogens, recent data indicate that these substances cannot account directly for the rapid production of PGE2 because it is initiated well before the synthase that they stimulate (cyclooxygenase-2, COX-2) becomes active. Moreover, cytokines also are not detectable in blood following i.v. LPS until after the febrile response is already underway, and there is no evidence that they can readily penetrate the brain. Hence, other, more quickly evoked mediators may be presumed to be involved in initiating the febrile response. Based on well-recognized mechanisms of LPS action, we have hypothesized that LPS virtually immediately activates the complement (C) cascade, generating the anaphylatoxins C3a and C5a, which function to activate macrophages and rapidly induce a mediator that has the capacity to stimulate peripheral sensory nerves that then transmit this information to the POA. We have data supporting the involvement of systemic C in the febrile response of guinea pigs to LPS, but more critical when LPS is injected i.p. than when it is administered iv. We hypothesize from preliminary data that this differential dependence on C may be related to distinct functional and biochemical characteristics of peritoneal and hepatic macrophages. Finally, recent preliminary data have suggested that the released mediator that acts on neural afferents may not be PGE2 and may also not be derived from macrophages, as had been supposed. The purpose of this proposed research, therefore, is to address the issues raised by our findings. The results will contribute to understanding the mechanisms of peripheral pyrogenic signaling, particularly regarding the onset of fever, as well as the processes that underlie the multivariate host defense reactions to infectious stimuli in general.
| Li, Shuxin; Dou, Wenkai; Tang, Ying et al. (2008) Acetaminophen: antipyretic or hypothermic in mice? In either case, PGHS-1b (COX-3) is irrelevant. Prostaglandins Other Lipid Mediat 85:89-99 |
| Blatteis, Clark M (2007) The onset of fever: new insights into its mechanism. Prog Brain Res 162:3-14 |
| Feleder, Carlos; Perlik, Vit; Blatteis, Clark M (2007) Preoptic nitric oxide attenuates endotoxic fever in guinea pigs by inhibiting the POA release of norepinephrine. Am J Physiol Regul Integr Comp Physiol 293:R1144-51 |
| Feleder, Carlos; Perlik, Vit; Blatteis, Clark M (2007) Preoptic norepinephrine mediates the febrile response of guinea pigs to lipopolysaccharide. Am J Physiol Regul Integr Comp Physiol 293:R1135-43 |
| Li, Zhonghua; Perlik, Vit; Feleder, Carlos et al. (2006) Kupffer cell-generated PGE2 triggers the febrile response of guinea pigs to intravenously injected LPS. Am J Physiol Regul Integr Comp Physiol 290:R1262-70 |
| Blatteis, Clark M (2006) Endotoxic fever: new concepts of its regulation suggest new approaches to its management. Pharmacol Ther 111:194-223 |
| Perlik, Vit; Li, Zhongua; Goorha, Sarita et al. (2005) LPS-activated complement, not LPS per se, triggers the early release of PGE2 by Kupffer cells. Am J Physiol Regul Integr Comp Physiol 289:R332-R339 |
| Blatteis, Clark M; Li, Shuxin; Li, Zhonghua et al. (2005) Cytokines, PGE2 and endotoxic fever: a re-assessment. Prostaglandins Other Lipid Mediat 76:1-18 |
| Li, S; Boackle, S A; Holers, V M et al. (2005) Complement component c5a is integral to the febrile response of mice to lipopolysaccharide. Neuroimmunomodulation 12:67-80 |
| Feleder, Carlos; Perlik, Vit; Tang, Ying et al. (2005) Putative antihyperpyretic factor induced by LPS in spleen of guinea pigs. Am J Physiol Regul Integr Comp Physiol 289:R680-7 |
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