The febrile response is thought to be mediated by endogenous mediators, generically called "endogenous pyrogens." In the classical model of pathogenesis, induction of fever is mediated by the release of pyrogenic cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, and interferons into the bloodstream in response to exogenous pyrogens.
Cytokines are highly inducible, secreted proteins mediating intercellular communication in the nervous and immune system. Fever is the multiphasic response of elevation and decline of the body core temperature regulated by central thermoregulatory mechanisms localized in the preoptic area of the hypothalamus. The discovery that several proinflammatory cytokines act as endogenous pyrogens and that other cytokines can act as antipyretic agents provided a link between the immune and the central nervous systems and stimulated the study of the central actions of cytokines. The proinflammatory cytokines interleukin 1 (IL-1), interleukin 6 (IL-6) and the tumor necrosis factor alpha (TNF) as well as the antiinflammatory cytokines interleukin 1 receptor antagonist (IL-1ra) and interleukin 10 (IL-10) have been most investigated for their pyrogenic or antipyretic action.
Studies performed at the end of the 1970s demonstrated that leukocytes, when stimulated with bacterial products, synthesize protein mediators called cytokines, some of which have potent EP-like properties. It thus became apparent that the EP activity in the plasma is represented by several of these cytokines with proinflam-matory properties: IL-1, TNF and lymphotoxin, IL-6, and IFNs. These proinflammatory cytokines reach the CNS where, through induction of central mediators such as prostaglandins (PGs), they are able to increase the temperature set point and cause fever. The increase in body temperature has several advantages during infections: it results in inhibition of bacterial growth, increased bactericidal activities of neutrophils and macrophages, stimulation of acute-phase protein synthesis, iron sequestration, anorexia, and somnolence.
IL-1 α and IL-1 β are considered to be the most important EPs. Injection of IL-1 into experimental animals has potent pyrogenic effects, and administration of an excess dose of IL-1 receptor antagonist (IL-1Rα) can prevent fever.
TNF is a proinflammatory cytokine that shares many bio-logic properties with IL-1. TNF injection induces a typical fever in rabbits that is indistinguishable from IL-1. More-over, TNF induces a second fever peak 3–4 h after challenge, which is suggested to be mediated through induction of endo-genous IL-1 production.
IL-6 is a cytokine initially described as a potent acute-phase protein inducer. It has been shown that IL-6 elicited fever when injected into rabbits and that IL-6 concentrations were correlated with fever in human patients with burns. Although one of the most potent proinflammatory properties of IL-6 is the stimulation of PG synthesis, IL-6 induction of fever in rabbits requires 50- to 100-fold higher amounts of IL-6 than of IL-1.
IFNs were described as antiviral substances, with potent immunostimulatory activities such as enhanced expression of class I and II major histocompatibility complex antigens and stimulation of natural killer activity. When injected into rabbits, IFNα induces a monophasic fever that peaks 80–90 min after the injection, which is mediated through induction of PG synthesis in the brain. IFNs were the first cytokines to be administered to humans, and fever was a constant side effect encountered with treatments with IFN-α, IFN- β, or IFN-γ.
Interleukin 10 (IL-10), originally known as cytokine synthesis inhibitory factor (CSIF), is an antiinflammatory cytokine and endogenous antipyretic produced by Th2 lymphocytes, monocytes, macrophages and other cell types. The antiinflammatory activity of IL-10 is mostly mediated by its effect on the inhibition of proinflammatory cytokines synthesis including IL-1, IL-6 and TNF. An IL-10 mediated suppression of both Gram negative and Gram positive bacteria induced increase in IL-6 concentrations was reported by Cartmell et al., suggesting a role of IL-10 in defervescence.
Several known cytokines induce fever in experimental animals, and one or more of them may be the EP produced in influenza virus infection. These cytokines include interleukin (IL)-1, IL-6, tumour necrosis factor (TNF)-α, interferon (IFN)-γ, IL-8, and macrophage inflammatory protein (MIP)-1α. The differences in fever produced by different strains may reflect differential induction of the same or different cytokines.
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