Early investigation of the nature of fever suggested the presence of a host-derived factor that resulted in elevation of body temperature. This was termed 'the endogenous pyrogen'. Initial studies demonstrated that interleukin 1 (IL-1) fulfilled many of the criteria of the endogenous pyrogen, but it has become apparent that several other cytokines also induce fever, in particular tumor necrosis factor, interferon-a, interferon-g, and interleukin 6 (IL-6). Therefore it would appear to be oversimplistic to consider a single cytokine as 'the endogenous pyrogen'.
Many animal studies have investigated the possible roles of different cytokines in initiating fever. Difficulties in interpreting such data arise at several points: considerable species differences exist, several cytokines have differing actions when administered systemically or locally in the central nervous system, activation of cytokines tends to occur as a cascade and thus one cytokine rarely acts in isolation, and most cytokines are pleiotropic with a great deal of functional overlap. In addition, it is not clear to what extent the presence of cytokines within the central nervous system is due to transport from the circulation across the blood-brain barrier, particularly at the organum vasculosum of the lamina terminalis, as opposed to local synthesis within the central nervous system.
Despite these difficulties, some consistent features can be observed. Cytokines act primarily on hypothalamic receptors; not infrequently, the 'neurotransmitter' released may be the same peptide as the cytokine that stimulated its release. Neurons producing mRNA for IL-1, IL-6, and tumor necrosis factor have been identified within the hypothalamus. Increased synthesis of IL-6 in the hypothalamus appears to be pivotal to the febrile response, and IL-6 receptors can be demonstrated in the preoptic hypothalamus. IL-6 probably represents a final common pathway for several cytokines. Thus IL-6-deficient mice fail to demonstrate a fever in response to lipopolysaccharide or IL-1. A schematic representation of the probable sequence of events is shown in Fig. 2. Although derived primarily from studies in small mammals, it is likely that a similar chain of cytokine signals prevails in humans ( Kluger.1996).
Fig. 2 Illustration of the probable sequence of events in the initiation of fever: OVLT, organum vasculosum of the lamina terminalis; CNS, central nervous system; TNF, tumor necrosis factor; LPS, lipopolysaccharide.
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