Pyrogenic signaling via vagal afferents: what stimulates their receptors?

Although there is good evidence that pyrogenic messages may be conveyed from the periphery to the brain via vagal afferents, the exact nature of the factors that activate their sensory terminals is unclear. Since IL-1beta and PGE2 have established roles in fever production and since their receptors have been identified on or near vagal nerves, they are potential candidate mediators. A difficulty, however, is that (1) IL-1beta is not expressed constitutively in mononuclear phagocytes, their presumed cell source upon stimulation by exogenous pyrogens, e.g. endotoxin, and (2) similarly, the isoform of the enzyme that selectively mediates the production and release of PGE2 by endotoxin-stimulated macrophages, COX-2, is also not constitutively expressed in these cells. Since the transcription and translation of these factors significantly lags the onset of fever induced by endotoxin administered intravenously, in particular, it is possible that a secondary, quickly-acting mediator evoked in almost immediate reaction to the presence of endotoxin excites, directly or indirectly, the sensory neurons. We have evidence that the complement component C5 contributes importantly to the initiation of the febrile response to endotoxin. This article briefly reviews the prevailing concepts of pyrogen sensing and signaling, examines their shortcomings particularly in terms of the temporal discrepancy between the very rapid onset of the febrile response to intravenously administered endotoxin and the significant delay in the elaboration of the putative mediators of fever, and presents newer data that may help to integrate the various preposed mechanisms.