Hirokawa J, Sakaue S, Furuya Y, Ishii J, Hasegawa A, Tagami S, Kawakami Y, Sakai M, Nishi S, Nishihira J
First Department of Medicine, Hokkaido University School of Medicine, Sapporo 060.
J Biochem. 1998 Apr;123(4):733-9. doi: 10.1093/oxfordjournals.jbchem.a021998.
Macrophage migration inhibitory factor (MIF) has been rediscovered as a proinflammatory cytokine, pituitary hormone, and glucocorticoid-induced immunoregulator. We have recently identified the expression of MIF in adipocytes and found that tumor necrosis factor (TNF)-alpha stimulates its secretion from 3T3-L1 adipocytes. Since adipocytes are regarded as a potential source of various biologically active substances, we examined in more detail the effect of TNF-alpha on MIF expression in 3T3-L1 adipocytes in the present study. We found that TNF-alpha induced MIF mRNA in dose- and time-dependent manners. After stimulation with TNF-alpha, the amount of intracellular MIF protein was unchanged or slightly decreased, concomitant with increased release of this protein into the extracellular space. This observation indicates that TNF-alpha stimulates MIF secretion from the constitutively expressed intracellular pool of 3T3-L1 adipocytes and promotes de novo synthesis of MIF. From evaluation of the mechanism of MIF gene expression, we found that tyrosine kinase inhibitors, either genistein or herbimycin A, suppressed the MIF mRNA induction by TNF-alpha. The results suggest the possibility that upregulation of MIF mRNA expression by TNF-alpha is mediated by a tyrosine kinase-dependent pathway. Taken together, the present observations shed light on the role of MIF in the metabolism of obesity and diabetes.
巨噬细胞移动抑制因子（MIF）已被重新发现是一种促炎细胞因子、垂体激素和糖皮质激素诱导的免疫调节因子。我们最近在脂肪细胞中鉴定出了MIF的表达，并发现肿瘤坏死因子（TNF）-α可刺激其从3T3-L1脂肪细胞中分泌。由于脂肪细胞被认为是各种生物活性物质的潜在来源，因此在本研究中，我们更详细地研究了TNF-α对3T3-L1脂肪细胞中MIF表达的影响。我们发现TNF-α以剂量和时间依赖性方式诱导MIF mRNA表达。在用TNF-α刺激后，细胞内MIF蛋白的量未发生变化或略有下降，同时该蛋白释放到细胞外空间的量增加。这一观察结果表明，TNF-α刺激3T3-L1脂肪细胞中组成型表达的细胞内池分泌MIF，并促进MIF的从头合成。通过对MIF基因表达机制的评估，我们发现酪氨酸激酶抑制剂染料木黄酮或除莠霉素A可抑制TNF-α诱导的MIF mRNA表达。结果提示，TNF-α上调MIF mRNA表达可能是通过酪氨酸激酶依赖性途径介导的。综上所述，本研究结果揭示了MIF在肥胖和糖尿病代谢中的作用。
