Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed

Abstract

For many years, it was thought that bacterial products caused fever via the intermediate production of a host-derived, fever-producing molecule, called endogenous pyrogen (EP). Bacterial products and other fever-producing substances were termed exogenous pyrogens. It was considered highly unlikely that exogenous pyrogens caused fever by acting directly on the hypothalamic thermoregulatory center since there were countless fever-producing microbial products, mostly large molecules, with no common physical structure. In vivo and in vitro, lipopolysaccharides (LPSs) and other microbial products induced EP, subsequently shown to be interleukin-1 (IL-1). The concept of the 'endogenous pyrogen' cause of fever gained considerable support when pure, recombinant IL-1 produced fever in humans and in animals at subnanomolar concentrations. Subsequently, recombinant tumor necrosis factor-alpha (TNF-alpha), IL-6 and other cytokines were also shown to cause fever and EPs are now termed pyrogenic cytokines. However, the concept was challenged when specific blockade of either IL-1 or TNF activity did not diminish the febrile response to LPS, to other microbial products or to natural infections in animals and in humans. During infection, fever could occur independently of IL-1 or TNF activity. The cytokine-like property of Toll-like receptor (TLR) signal transduction provides an explanation by which any microbial product can cause fever by engaging its specific TLR on the vascular network supplying the thermoregulatory center in the anterior hypothalamus. Since fever induced by IL-1, TNF-alpha, IL-6 or TLR ligands requires cyclooxygenase-2, production of prostaglandin E2 (PGE2) and activation of hypothalamic PGE2 receptors provides a unifying mechanism for fever by endogenous and exogenous pyrogens. Thus, fever is the result of either cytokine receptor or TLR triggering; in autoimmune diseases, fever is mostly cytokine mediated whereas both cytokine and TLR account for fever during infection.

Effect of a Convenient Single 90-mg Pamidronate Dose on Biochemical Markers of Bone Metabolism in Patients With Acute Spinal Cord Injury

“…Pamidronate-stimulated cd T cells results in variable dose-dependent tumor necrosis factor (TNF)-a and interferon-c (IFN) release patterns and inhibition of bone resorption (34)(35)(36)(37)(38). TNF-a, as well as other cytokines, also interacts with hypothalamic thermoregulatory centers causing temperature elevation (39). In addition, patients with SCI have impaired autonomic nervous system function below the level of injury that results in reduced sweat capacity (40) and blood flow (41).…”

Inflammatory caspases and inflammasomes: master switches of inflammation

“…16 IL-1b is a major mediator of inflammation and, in general, initiates and/or amplifies a wide variety of effects associated with innate immunity and host responses to microbial invasion and tissue injury. 17 When mice are immunized with protein antigens together with IL-1b, serum antibody production is enhanced, suggesting that IL-1b has adjuvant properties. 18 On the other hand, the physiological role of IL-1b adjuvanticity and costimulation of T cells has not been fully established.…”

The many worlds of reducing interleukin‐1

“…Although it is often difficult to demonstrate elevated circulating levels of IL-1␤ in these patients, the rapid reduction in fever, neutrophilia, and acute-phase reactants by anakinra demonstrates that these are IL-1-mediated diseases, since IL-1Ra blocks only the IL-1 receptor. IL-1 is the most pyrogenic of the feverinducing cytokines (17); morever, IL-1 is a bone marrow stimulant, particularly of neutrophilic responses (18). In contrast, TNF␣ suppresses bone marrow functions.…”