Morohoshi M, Fujisawa K, Uchimura I, Numano F
Third Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
Diabetes. 1996 Jul;45(7):954-9. doi: 10.2337/diab.45.7.954.
To clarify the mechanisms that cause elevation of plasma fibrinogen levels in diabetes, we first examined the effect of hyperglycemia on the production of interleukin 6 (IL-6) and tumor necrosis factor (TNF) by cultured human peripheral blood monocytes. Monocyte-enriched fractions isolated from 20 healthy volunteers were incubated with 11 mmol/l glucose, 33 mmol/l glucose, or mannitol as an osmolar control for 6 or 24 h. After 6 h of incubation, IL-6 and TNF-alpha mRNA levels were analyzed by reverse transcription and polymerase chain reaction. In addition, after 24 h of incubation, IL-6 and TNF-alpha immunoreactivity in the culture medium was measured by enzyme-linked immunoassay. Both IL-6 and TNF-alpha mRNA levels and immunoreactivity were significantly increased by treatment with 33 mmol/l glucose compared with treatment with 11 mmol/l glucose or 11 mmol/l glucose with 22 mmol/l mannitol. In addition, preincubation of the cells with an anti-TNF monoclonal antibody (mAb) blocked the stimulatory effect of 33 mmol/l glucose on IL-6 synthesis and secretion. Second, we examined the ability of conditioned media from human peripheral blood monocytes to stimulate beta-fibrinogen mRNA synthesis in HepG2 cells. The conditioned medium from monocytes treated with 33 mmol/l glucose increased beta-fibrinogen mRNA levels. The results of this study demonstrate that hyperglycemia stimulated IL-6 and TNF synthesis and secretion by human peripheral monocytes in vitro and that the IL-6 response to hyperglycemia may be mediated by TNF. Furthermore, hyperglycemia may increase fibrinogen levels through stimulation of peripheral monocytes. These results suggest that hyperglycemia may cause hyperfibrinogenemia in diabetic patients through an IL-6-dependent and TNF-dependent mechanism.
为阐明糖尿病患者血浆纤维蛋白原水平升高的机制，我们首先研究了高血糖对培养的人外周血单核细胞产生白细胞介素6（IL-6）和肿瘤坏死因子（TNF）的影响。从20名健康志愿者中分离出富含单核细胞的组分，分别与11 mmol/l葡萄糖、33 mmol/l葡萄糖或作为渗透压对照的甘露醇孵育6或24小时。孵育6小时后，通过逆转录和聚合酶链反应分析IL-6和TNF-α mRNA水平。此外，孵育24小时后，通过酶联免疫吸附测定法测量培养基中IL-6和TNF-α的免疫反应性。与11 mmol/l葡萄糖或11 mmol/l葡萄糖加22 mmol/l甘露醇处理相比，33 mmol/l葡萄糖处理显著增加了IL-6和TNF-α mRNA水平及免疫反应性。此外，用抗TNF单克隆抗体（mAb）预孵育细胞可阻断33 mmol/l葡萄糖对IL-6合成和分泌的刺激作用。其次，我们研究了人外周血单核细胞条件培养基刺激HepG2细胞中β-纤维蛋白原mRNA合成的能力。用33 mmol/l葡萄糖处理的单核细胞的条件培养基增加了β-纤维蛋白原mRNA水平。本研究结果表明，高血糖在体外刺激人外周单核细胞合成和分泌IL-6和TNF，并且IL-6对高血糖的反应可能由TNF介导。此外，高血糖可能通过刺激外周单核细胞增加纤维蛋白原水平。这些结果提示，高血糖可能通过依赖IL-6和TNF的机制导致糖尿病患者出现高纤维蛋白原血症。
