Beutler B, Greenwald D, Hulmes J D, Chang M, Pan Y C, Mathison J, Ulevitch R, Cerami A
Nature. 1985;316(6028):552-4. doi: 10.1038/316552a0.
In mammals, several well-defined metabolic changes occur during infection, many of which are attributable to products of the reticuloendothelial system. Among these changes, a hypertriglyceridaemic state is frequently evident, resulting from defective triglyceride clearance, caused by systemic suppression of the enzyme lipoprotein lipase (LPL). We have found previously that macrophages secrete the hormone cachectin, which specifically suppresses LPL activity in cultured adipocytes (3T3-L1 cells). When originally purified from RAW 264.7 (mouse macrophage) cells, cachectin was shown to have a pI of 4.7, a subunit size of relative molecular mass (Mr) 17,000 and to form non-covalent multimers. A receptor for cachectin was identified on non-tumorigenic cultured cells and on normal mouse liver membranes. A new high-yield purification technique has enabled us to determine further details of the structure of mouse cachectin. We now report that a high degree of homology exists between the N-terminal sequence of mouse cachectin and the N-terminal sequence recently determined for human tumour necrosis factor (TNF). Purified cachectin also possesses potent TNF activity in vitro. These findings suggest that the 'cachectin' and 'TNF' activities of murine macrophage conditioned medium are attributable to a single protein, which modulates the metabolic activities of normal as well as neoplastic cells through interaction with specific high-affinity receptors.
在哺乳动物中，感染期间会发生几种明确的代谢变化，其中许多变化归因于网状内皮系统的产物。在这些变化中，高甘油三酯血症状态经常很明显，这是由于脂蛋白脂肪酶（LPL）受到全身抑制导致甘油三酯清除缺陷所致。我们之前发现巨噬细胞分泌恶病质素，它能特异性抑制培养的脂肪细胞（3T3-L1细胞）中的LPL活性。最初从RAW 264.7（小鼠巨噬细胞）细胞中纯化出来时，恶病质素的pI为4.7，亚基大小为相对分子质量（Mr）17,000，并形成非共价多聚体。在非致瘤性培养细胞和正常小鼠肝细胞膜上鉴定出了恶病质素受体。一种新的高产纯化技术使我们能够进一步确定小鼠恶病质素的结构细节。我们现在报告，小鼠恶病质素的N端序列与最近确定的人肿瘤坏死因子（TNF）的N端序列存在高度同源性。纯化的恶病质素在体外也具有强大的TNF活性。这些发现表明，小鼠巨噬细胞条件培养基的“恶病质素”和“TNF”活性归因于一种单一蛋白质，该蛋白质通过与特定的高亲和力受体相互作用来调节正常细胞和肿瘤细胞的代谢活动。
