The afferent signalling of fever

When infectious micro-organisms invade the body, fever often ensues. It is the most familiar and most manifest sign of infection. Yet, despite its ubiquity, little is definitively known regarding the detailed mechanism of its induction. The generally prevalent view is that entry into the body of such infectious micro-organisms first activates innate immune responses, which include the release of a complex variety of soluble mediators. Among these, the cytokines tumour necrosis factor (TNF) alpha, interleukin (IL)-1beta and IL-6 are thought to convey the pyrogenic message to the brain region where fever is regulated, namely the preoptic area (POA) of the anterior hypothalamus. The mechanism by which these peripheral signals may be transduced into central nervous signals is currently a matter of lively controversy. The issue is not trivial because, to the extent that these relatively large, hydrophilic peptides may be released into the circulatory system and transported to the brain by the bloodstream, they have to pass through the blood-brain barrier (BBB), which is impermeable to them. At least two routes are possible, and there is evidence for both: (1) active transport across the BBB by cytokine-specific carriers, and (2) message transfer where the BBB is 'leaky', i.e. in the 'sensory' circumventricular organs, particularly the organum vasculosum laminae terminalis (OVLT), on the midline of the POA, by the presumptive activation by, an as yet, indeterminate means of neurons projecting into the OVLT from the brain. But alternative pathways are also possible and support for some has been obtained: (1) the circulating cytokine-induced generation of BBB-permeable prostaglandin E2, the most proximal, putative mediator of fever, by endothelial cells of the cerebral microvasculature or perivascular microglia and meningeal macrophages, and (2) direct transmission to the POA of the pyrogenic messages via peripheral (largely vagal) afferent nerves activated by the cytokines. However, all four of these mechanisms have shortcomings (Blatteis & Sehic, 1997).