title: 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)
mesh_terms: D000818:Animals; D015232:Dinoprostone; D004731:Endotoxins / Q000633:toxicity; D005334:Fever / Q000139:chemically induced*; D006023:Glycoproteins / Q000494:pharmacology / Q000633:toxicity*; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000633:toxicity; D051379:Mice; D009000:Monocytes / Q000187:drug effects; D011458:Prostaglandins E / Q000096:biosynthesis; D011749:Pyrogens / Q000494:pharmacology / Q000633:toxicity*; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology / Q000633:toxicity; D013268:Stimulation, Chemical; D014409:Tumor Necrosis Factor-alpha
chemical_list: D004731:Endotoxins; D006023:Glycoproteins; D007375:Interleukin-1; D011458:Prostaglandins E; D011749:Pyrogens; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D015232:Dinoprostone