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

机译:肿瘤坏死因子(cachectin)是一种内源性热原,可诱导白介素1的产生

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摘要

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)
机译:静脉内注射到兔中的重组人肿瘤坏死因子(rTNF alpha)产生了与rIL-1产生的发烧没有区别的快速发作的单相发烧。以重量计(1微克/千克),rTNFα和rIL-1产生相同的发烧量,并在体外诱导兔下丘脑细胞中PGE2水平相当;像IL-1一样,TNF发烧被抑制环氧合酶的药物阻断。在较高剂量(10微克/千克)下,rTNFα产生双相热。推注后45-55分钟,第一次发烧达到高峰,可能代表了对温度调节中心的直接作用。在第二次发烧高峰期(3小时后),通过将血浆被动转移到新鲜兔子中,可以显示存在循环内源性热原。这可能代表了IL-1的体内诱导。在体外,rTNFα诱导人单核细胞释放IL-1活性,在50-100 ng / ml rTNFα时观察到最大产量。另外,rTNFα和rIFN-γ对IL-1产生具有协同作用。 rTNFα的生物学活性可以通过三种方式与IL-1区别:rIL-1的单相热解活性在70摄氏度时被破坏,而rTNFα仍保持活性。抗IL-1可以中和IL-1,但不能识别rTNFα或天然恶臭素,也不能中和其细胞毒性作用;与IL-1不同,rTNFα在有丝分裂原刺激的T细胞增殖试验中没有活性。几项研究排除了内毒素引起rTNFα发烧和/或IL-1诱导的可能性:rTNFα在耐内毒素的C3H / HeJ小鼠中产生发烧; rTNFα的IL-1诱导特性被加热(70摄氏度)或胰蛋白酶消化破坏,不受多粘菌素B的影响;没有发生每日注射rTNFα的热原耐受性; eb变形细胞溶解物中测定的内毒素水平低于兔子热原最低剂量;并且通过气相色谱/质谱分析法确认了β-羟基肉豆蔻酸的存在,证实了这些内毒素水平。尽管rTNFα在T细胞增殖测定中没有活性,但它可能在T细胞测定中模拟IL-1,因为高浓度的rTNFα诱导了胸腺细胞制剂中上皮细胞或巨噬细胞的IL-1。这些研究表明,TNF(cachectin)是另一种内源性热原,它像IL-1和IFN-α一样直接刺激下丘脑PGE2的合成。另外,rTNFα是IL-1的内源性诱导剂。(摘要截短为400字)

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