Systemic Delivery of TNF-Related Apoptosis-Inducing Ligand (TRAIL) Elevates Levels of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) and Prevents Type 1 Diabetes in Nonobese Diabetic Mice
Systemic Delivery of TNF-Related Apoptosis-Inducing Ligand (TRAIL) Elevates Levels of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) and Prevents Type 1 Diabetes in Nonobese Diabetic Mice
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DOI：
10.1210/en.2009-0478
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发表时间：
2010-12-01
期刊：
影响因子：
4.8
通讯作者：
Lee, Hye-Jeong
中科院分区：
文献类型：
--
作者：
Kang, Soojeong;Park, Eun-Jin;Lee, Hye-Jeong
最近的研究表明，肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种免疫反应的调节剂。TRAIL与1型糖尿病（T1 D）作为体内自身免疫性炎症性疾病之间的关系相对未知。为了探索TRAIL在T1 D发展中的潜在作用，我们研究了其在非肥胖糖尿病（NOD）小鼠中的体内作用。用携带人TRAIL（Ad.hTRAIL）或β-半乳糖苷酶基因的腺病毒静脉注射7周龄的NOD小鼠。每周监测血糖，并评估小鼠血浆和肝脏中hTRAIL的表达。为了研究hTRAIL是否通过诱导金属蛋白酶组织抑制因子-1（TIMP-1）来发挥其作用，我们用ELISA法检测了血浆TIMP-1的浓度，用明胶酶谱法检测了对基质金属蛋白酶（MMP）的抑制。在这里，我们表明，Ad. hTRAIL转导的小鼠有显着降低血糖水平和显着增加TIMP-1的生产相比，控制β-半乳糖苷酶的动物。从Ad. hTRAIL处理的NOD小鼠显示MMP活性降低，与显著改善的胰岛炎相关。此外，TIMP-1在体外抑制了精氨酸诱导的产生胰岛素的INS-1细胞凋亡。这些结果表明，T1 D可以通过TRAIL过表达通过增强TIMP-1功能来预防。TIMP-1产生的升高抑制MMPs的活性，这可能有助于抑制致糖尿病性T细胞迁移到胰岛中并保护胰腺β细胞免受甘氨酸诱导的凋亡。因此，TRAIL和TIMP-1诱导可能是预防T1 D发展的潜在靶点。（内分泌学151：5638-5646，2010）
Recent studies have demonstrated that TNF-related apoptosis-inducing ligand (TRAIL) is a modulator of the immune response. The relation between TRAIL and type 1 diabetes (T1D) as an autoimmune inflammatory disease in vivo is relatively unknown. To explore the potential role of TRAIL in the development of T1D, we examined its in vivo effects in nonobese diabetic (NOD) mice. NOD mice at 7 wk of age were iv injected with an adenovirus carrying either human TRAIL (Ad.hTRAIL) or beta-galactosidase genes. Blood glucose was monitored weekly, and the expression of hTRAIL was evaluated in plasma and liver of mice. To investigate whether hTRAIL elicits its effect through the induction of tissue inhibitor of metalloproteinase-1 (TIMP-1), we examined the concentration of plasma TIMP-1 by ELISA and the inhibition of matrix metalloproteinase (MMP) by gelatin zymography. Here, we show that Ad.hTRAIL-transduced mice had significantly reduced blood glucose levels and markedly increased production of TIMP-1 compared with control beta-galactosidase animals. Pancreatic tissue isolated from Ad. hTRAIL-treated NOD mice showed reduced MMP activities associated with significantly improved insulitis. In addition, TIMP-1 in vitro suppressed cytokine-induced apoptosis in insulin-producing INS-1 cells. These results indicate that T1D can be prevented by TRAIL overexpression through enhancement of TIMP-1 function. Elevated TIMP-1 production inhibits the activity of MMPs, which may contribute to suppress the transmigration of diabetogenic T cells into the pancreatic islets and protects pancreatic beta-cells from cytokine-induced apoptosis. Therefore, TRAIL and TIMP-1 induction may be potential targets to prevent development of T1D. (Endocrinology 151: 5638-5646, 2010)