Sewter C P, Digby J E, Blows F, Prins J, O'Rahilly S
Departments of Medicine and Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
J Endocrinol. 1999 Oct;163(1):33-8. doi: 10.1677/joe.0.1630033.
Tumour necrosis factor-alpha (TNF-alpha), secreted by cells of the macrophage-monocyte lineage, has a well established role in inflammation and host-defence. The more recent discovery that adipocytes also secrete TNF-alpha has led to a substantial body of research implicating this molecule in the insulin resistance of obesity. However, little is known about the normal regulation of TNF-alpha release from human adipose tissue. In particular, it is not known whether adipocyte production of TNF-alpha is responsive to similar or different molecular regulators than those relevant to macrophages. TNF-alpha release from cultured human adipose tissue and isolated adipocytes was examined using an ELISA. Insulin, cortisol or the thiazolidinedione, BRL 49653, did not have a significant effect on TNF-alpha release from adipose tissue or isolated adipocytes. In contrast, lipopolysaccharide (LPS), a major stimulus of TNF-alpha protein production in monocytes and macrophages, resulted in a fivefold stimulation of TNF-alpha release from human adipose tissue. Significant stimulation of TNF-alpha release was also seen from isolated adipocytes, indicating that the increase in TNF-alpha release from adipose tissue in the presence of LPS is unlikely to be entirely attributable to contaminating monocytes or macrophages. Consistent with this observation was the finding that mRNA for CD14, a known cellular receptor for LPS, is expressed in human adipocytes. The increase in TNF-alpha protein release in response to LPS was blocked by an inhibitor of the matrix metalloproteinase responsible for the cleavage of the membrane-bound proform of TNF-alpha, indicating that this release represented regulated secretion and was not due to cell lysis. In conclusion, the regulation of TNF-alpha protein release from human adipose tissue and isolated adipocytes appears to be similar to its regulation in cell types more traditionally implicated in host defence. The production by the adipocyte of a range of molecules involved in host defence-TNF-alpha, factors D, B and C3, interleukin-6, and macrophage colony-stimulating factor--suggest that this cell type may make a significant contribution to innate immunity.
肿瘤坏死因子-α（TNF-α）由巨噬细胞-单核细胞谱系的细胞分泌，在炎症和宿主防御中具有公认的作用。最近发现脂肪细胞也分泌TNF-α，这引发了大量研究，表明该分子与肥胖的胰岛素抵抗有关。然而，关于人脂肪组织中TNF-α释放的正常调节知之甚少。特别是，尚不清楚脂肪细胞产生的TNF-α是否对与巨噬细胞相关的分子调节因子有类似或不同的反应。使用酶联免疫吸附测定法（ELISA）检测了培养的人脂肪组织和分离的脂肪细胞中TNF-α的释放。胰岛素、皮质醇或噻唑烷二酮类药物BRL 49653对脂肪组织或分离的脂肪细胞中TNF-α的释放没有显著影响。相比之下，脂多糖（LPS）是单核细胞和巨噬细胞中TNF-α蛋白产生的主要刺激物，可使人脂肪组织中TNF-α的释放增加五倍。从分离的脂肪细胞中也观察到TNF-α释放的显著刺激，这表明在LPS存在下脂肪组织中TNF-α释放的增加不太可能完全归因于污染的单核细胞或巨噬细胞。与这一观察结果一致的是，在人脂肪细胞中发现了脂多糖的已知细胞受体CD14的信使核糖核酸（mRNA）。负责切割膜结合前体形式的TNF-α的基质金属蛋白酶抑制剂可阻断LPS诱导的TNF-α蛋白释放增加，这表明这种释放代表了调节性分泌，而不是由于细胞裂解。总之，人脂肪组织和分离的脂肪细胞中TNF-α蛋白释放的调节似乎与其在更传统地参与宿主防御的细胞类型中的调节相似。脂肪细胞产生一系列参与宿主防御的分子——TNF-α、因子D、B和C3、白细胞介素-6以及巨噬细胞集落刺激因子——表明这种细胞类型可能对先天免疫做出重大贡献。
