Fever

Robert B Ashman, Department of Pathology, University of Western Australia, Nedlands, Australia

Since the writings of Hippocrates, fever has been autogenous pus could cause fever when inoculated almost universally recognized as a manifestation of into rats; however, at the time this observation was disease. A linkage between the two was formally made, the pyrogenic activity of bacterial endotoxins established by the demonstration that filtrates of was unsuspected. The existence of an endogenous pyrogen was definitively established in 1953, when Bennett and Beeson showed that leukocytes contain a factor that induces fever in the absence of infection. Subsequently, a moiety with activity similar to that of the leukocyte pyrogen was found in the serum of animals that developed fevers after inoculation of various microbial agents. The bacterial and endogenous pyrogens were not identical, as the former disappeared rapidly from the circulation, whereas titers of endogenous pyrogen increased, and showed a good correlation with the course of the ensuing fever. The induction of fever in conjunction with hypersensitivity responses, and the passive transfer of a fever-inducing substance in the serum of sensitized animals, clearly confirmed the endogenous origin of the pyrogen. Other organisms, such as gram-positive bacteria and viruses, can also induce fevers, the kinetics of which differ in some respects from those induced by bacterial endotoxin.

Endogenous pyrogens

Leukocytes, and macrophages in particular, produce a variety of cytokines that often exhibit similar or overlapping biological activities. Many of these have been shown to induce fever either directly or by the induction of other endogenous pyrogens. Although the use of recombinant material has clarified the specific functions and pyrogenic activities of the various species, their interrelationships are very complex, as they can induce their own - and each other's - production both in vitro and in vivo. The mechanisms that regulate these interactions have not been unraveled, but may involve inhibitory effects of prostaglandins on the synthesis of endogenous pyrogens. The major pyrogenic cytokines are briefly described below.

Interleukin 1

Although several cytokines have now been shown to induce fever in vivo, interleukin 1 (IL-1) is most likely to represent the molecule(s) originally described as the endogenous pyrogen. Two genes have been identified that code for two different forms of IL-1: IL-la and IL-jS. Although the two forms of IL-1 exhibit only limited homology (<27%), both are translated as 31 kDa precursor peptides. These peptides lack a cleavage sequence, implying that an enzymatic step is required for processing of the precursor molecule to its mature form. Consequently, a proportion of the translated protein remains associated with the cell as the high molecular weight precursor. The biological activities of IL-a and IL-j3 arc for the most part identical, implying that the short regions of sequence homology represent active sites common to both forms. Analysis of recombinant IL-1 molecules has shown that both a 24.5 kDa and a 17.3 kDa peptide evoke monophasic fevers when injected into rabbits; however, the smaller peptide is approximately 100 times more active than the larger. This is consistent with the concept that a large, relatively inactive precursor is processed to a smaller, biologically active form. However, there may be more than one active moiety, as a 4 kDa peptide has also been shown to cause fever.

Tumor necrosis factor

Tumor necrosis factor (TNF) is a macrophage product that produces a classical endogenous pyrogen fever in rabbits and mice. Its biological activity is similar to that of IL-1, in that 50-200 ng kg 1 of either factor induces comparable febrile responses. However, injection of larger quantities evokes a second peak, and there is evidence that TNF induces IL-1 both in vitro and in vivo. Another cytokine, lymphotoxin, shows considerable homology with TNF, and this substance also induces IL-1, and produces fever in animals.

Interferons

Interferons (IFNs) were originally described as antiviral agents, but they have been found to possess a wide range of biological activities, including pyro-genicity. However, substantially more recombinant human (rh) IFNa than rhTNF or rhll.-l is required to induce a fever in rabbits, although this difference can perhaps be attributed to the species specificity exhibited by the interferons. IFN/3 and IFNy are both pyrogenic for humans, though somewhat less so than IFNa. IFNa and IFN/3 show considerable amino acid homology, but IFNy is quite distinct, and the mechanism of fever induction by the latter may also be different.

Interleukin 2

Interleukin 2 (ÍL-2) is known to cause fever in humans. Its half-life in the peripheral circulation is very brief, so it probably acts by stimulating the production or release of other endogenous pyrogens or pyrogenic prostaglandins.

Macrophage inflammatory protein 1 (MIP-1)

This cytokine has been cloned and sequenced, and is composed of two distinct but highly homologous proteins, the separate functions of which have not yet been characterized. MIP-l is secreted in response to endotoxin, elicits localized inflammatory responses, is chemotactic for human neutrophils, and activates these cells for an oxidative burst. It also induces a monophasic fever of rapid onset, approximately equal in magnitude to that induced by rhTNF or rhIL-1. However, the fever induced by M1P-1 is nor blocked by cyclo-oxygenase inhibitors, so it is apparently initiated by a pathway that does not involve synthesis of prostaglandins.

Mechanism of fever induction

The control of body temperature resides in the hypothalamus, which is a primitive part of the brainstem that regulates certain bodily functions, such as sleep, and that also secretes a number of neuroendocrine-releasing factors. The anterior hypothalamus contains thermosensitive neurons, whose response is affected both by the temperature of the blood and by neural connections with peripheral temperature receptors. Provided that the mechanisms governing heat production and heat loss are intact, fever results from a resetting of the thermoregulatory centre in the hypothalamus to a higher level.

The crucial step in the induction of fever appears to involve increases in the production of arachidonic acid metabolites, especially prostaglandin E2 (PGE2). Several different lines of evidence favour a role for PGE2 as the neural mediator in the febrile response. Antipyretics such as ibuprofen and indomethacin are potent inhibitors of prostaglandin synthesis; cytokines such as IL-1, TNF, and IFNa all stimulate PGE2 production from hypothalamic tissue in vitro; and injection of PGE2 directly into the hypothalamus induces fever within minutes. Thus, current concepts envisage the febrile response being initiated by the production and release of endogenous pyrogens as a consequence of an infection, an inflammatory response, or an immunologically mediated disease. The pyrogenic immunomodulators increase the level of PGE2 in the blood, and this mediator, as well as endogenous pyrogens such as II -1 and TNF, act on the hypothalamus to induce fever. Brain regions sensitive to the direct effect of endogenous pyrogen are restricted to regions near the organum vasculo-sum laminae terminalis (OVLT), whereas the nucleus Broca ventralis, preoptic area, and the anterior and ventromedial hypothalamus, are able to respond directly to injections of small doses of prostaglandins E2 and F2. The ventromedial region of the hypothalamus is the area most sensitive to PGE2, as measured by the induction of fever in rabbits.

The different sites of action of the different mediators show that there exist two separate pathways for induction of fever. First of all. prostaglandins synthesized outside the blood-brain barrier act on multiple sites in the central nervous system to induce rapid-onset fever. In contrast, although the endogenous pyrogens have the effect of stimulating release of arachidonic acid metabolites from the hypothalamus in vitro, there is no direct evidence that they cross the blood-brain barrier. Their actions are probably concentrated in the vicinity of the OVI.T, inducing the synthesis and release of pyrogenic prostaglandins that produce a secondary peak of fever (Figure 1). There is no evidence that prostaglandins can, of themselves, act as neurotransmitters; but they are known to increase levels of cyclic A.VIP, which can perform this function. Prostaglandins certainly play a central part in the induction of fever, but there exists at least one prostaglandin-inde-pendent pathway, as demonstrated by the pyrogen it-action of MIP-1. The relative importance in vivo of

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