Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1.

Abstract

Recombinant human tumor necrosis factor (rTNF alpha) injected intravenously into rabbits produces a rapid-onset, monophasic fever indistinguishable from the fever produced by rIL-1. On a weight basis (1 microgram/kg) rTNF alpha and rIL-1 produce the same amount of fever and induce comparable levels of PGE2 in rabbit hypothalamic cells in vitro; like IL-1, TNF fever is blocked by drugs that inhibit cyclooxygenase. At higher doses (10 micrograms/kg) rTNF alpha produces biphasic fevers. The first fever reaches peak elevation 45-55 min after bolus injection and likely represents a direct action on the thermoregulatory center. During the second fever peak (3 h later), a circulating endogenous pyrogen can be shown present using passive transfer of plasma into fresh rabbits. This likely represents the in vivo induction of IL-1. In vitro, rTNF alpha induces the release of IL-1 activity from human mononuclear cells with maximal production observed at 50-100 ng/ml of rTNF alpha. In addition, rTNF alpha and rIFN-gamma have a synergistic effect on IL-1 production. The biological activity of rTNF alpha could be distinguished from IL-1 in three ways: the monophasic pyrogenic activity of rIL-1 was destroyed at 70 degrees C, whereas rTNF alpha remained active; anti-IL-1 neutralized IL-1 but did recognize rTNF alpha or natural cachectin nor neutralize its cytotoxic effect; and unlike IL-1, rTNF alpha was not active in the mitogen-stimulated T cell proliferation assay. The possibility that endotoxin was responsible for rTNF alpha fever and/or the induction of IL-1 was ruled-out in several studies: rTNF alpha produced fever in the endotoxin-resistant C3H/HeJ mice; the IL-1-inducing property of rTNF alpha was destroyed either by heat (70 degrees C) or trypsinization, and was unaffected by polymyxin B; pyrogenic tolerance to daily injections of rTNF alpha did not occur; levels of endotoxin, as determined in the Limulus amebocyte lysate, were below the minimum rabbit pyrogen dose; and these levels of endotoxin were confirmed by gas chromatography/mass spectrometry analysis for the presence of beta-hydroxymyristic acid. Although rTNF alpha is not active in T cell proliferation assays, it may mimic IL-1 in a T cell assay, since high concentrations of rTNF alpha induced IL-1 from epithelial or macrophagic cells in the thymocyte preparations. These studies show that TNF (cachectin) is another endogenous pyrogen which, like IL-1 and IFN-alpha, directly stimulate hypothalamic PGE2 synthesis. In addition, rTNF alpha is an endogenous inducer of IL-1.(ABSTRACT TRUNCATED AT 400 WORDS)

Therapeutic effect of Yunnan Baiyao on rheumatoid arthritis was partially due to regulating arachidonic acid metabolism in osteoblasts

“…Serum IL-1␤ was also regulated by YNB (Fig. 2) and IL-1␤ positively affected the synthesis of PGE 2 [26]. This study also raised a new question that how YNB functionally coordinates the interactions between PGE 2 and IL-1␤.…”

Behavioral fever in ectothermic vertebrates

“…These PRR are expressed by innate immune cells including macrophages, dendritic cells and neutrophils and upon activation, trigger proinflammatory and antimicrobial reactions (Mogensen, 2009). Notably, their activation induces the release of pyrogenic cytokines called endogenous pyrogens such as interleukin (IL) 1b, IL6, tumor necrosis factor a (TNFa), and interferons (IFN) (Dinarello, 1999;Netea et al, 2000). Both IL1b and TNFa can induce the expression of each other (Dinarello et al, 1986;Ikejima et al, 1990) and are potent inducers of IL6 (Zetterstrom et al, 1998), which on contrary tends to be an inhibitor of IL1b and TNFa production (Netea et al, 2000;Schindler et al, 1990).…”

“…Notably, their activation induces the release of pyrogenic cytokines called endogenous pyrogens such as interleukin (IL) 1b, IL6, tumor necrosis factor a (TNFa), and interferons (IFN) (Dinarello, 1999;Netea et al, 2000). Both IL1b and TNFa can induce the expression of each other (Dinarello et al, 1986;Ikejima et al, 1990) and are potent inducers of IL6 (Zetterstrom et al, 1998), which on contrary tends to be an inhibitor of IL1b and TNFa production (Netea et al, 2000;Schindler et al, 1990). IL6 seems to be the major mediator for sustaining fever; indeed, IL6-knockout mice or IL6-neutralizing antibodiesinjected mice were not able to develop LPS-induced fever, even if TNFa and IL1b upregulation was unaltered (Chai et al, 1996;Hamzic et al, 2013;Kozak et al, 1998).…”

Inflammatory caspases and inflammasomes: master switches of inflammation

“…Recombinant IL-1b induces fever in experimental animals, an activity shared with other cytokines including tumor necrosis factor (TNF) and IL-6, although the latter cytokines are much less potent than IL-1b. 19 In addition to fever, IL-1b has other effects on the central nervous system. These include induction of slow-wave sleep, anorexia and inflammatory pain hypersensitivity, typically associated with infections or injury.…”