PDF(Pubmed)
Abstract：
Type 1 diabetes mellitus (T1DM) development involves a complex interplay of genetic, environmental, and immunological factors. By modulating the activity of proteases and receptors, the protein tissue inhibitor of metalloproteinase 3 (TIMP3) plays a role in limiting the expression and function of pro-inflammatory cytokines, which have been implicated in the advancement of T1DM. This study was aimed at examining the effect of TIMP3 overexpression in myeloid cells on the development of T1DM.
Twelve weeks after multiple low doses of streptozotocin (MLDS) treatment, diabetic mice overexpressing TIMP3 specifically in myeloid cells under the CD68 promoter (MacT3 mice) showed improved insulin secretion, islet morphology and vascularization, antioxidant defense system, and regulatory factors of mitochondrial biosynthesis and function. To get mechanistic insights into the origin of this protection, the severity of insulitis and inflammatory parameters were evaluated in pancreatic tissues 11 days after MLSD treatment, showing significantly reduced insulitis and levels of the pro-inflammatory cytokine tumor necrosis factor-α, interleukin -1β, and interferon -γ in MacT3 mice.
The results indicate that TIMP3 is involved in maintaining islet architecture and functions, at least in part, through modulation of pro-inflammatory cytokine production associated with insulitis and may represent a novel therapeutic strategy for T1DM.
Twelve weeks after multiple low doses of streptozotocin (MLDS) treatment, diabetic mice overexpressing TIMP3 specifically in myeloid cells under the CD68 promoter (MacT3 mice) showed improved insulin secretion, islet morphology and vascularization, antioxidant defense system, and regulatory factors of mitochondrial biosynthesis and function. To get mechanistic insights into the origin of this protection, the severity of insulitis and inflammatory parameters were evaluated in pancreatic tissues 11 days after MLSD treatment, showing significantly reduced insulitis and levels of the pro-inflammatory cytokine tumor necrosis factor-α, interleukin -1β, and interferon -γ in MacT3 mice.
The results indicate that TIMP3 is involved in maintaining islet architecture and functions, at least in part, through modulation of pro-inflammatory cytokine production associated with insulitis and may represent a novel therapeutic strategy for T1DM.
摘要：
■1型糖尿病（T1DM）的发展涉及复杂的遗传相互作用，环境,和免疫因素。通过调节蛋白酶和受体的活性，金属蛋白酶组织抑制因子3(TIMP3)在限制促炎细胞因子的表达和功能中发挥作用,这与T1DM的进展有关。本研究旨在研究骨髓细胞中TIMP3过表达对T1DM发展的影响。
■多次低剂量链脲佐菌素（MLDS）治疗12周后，在CD68启动子下的骨髓细胞中特异性过度表达TIMP3的糖尿病小鼠（MacT3小鼠）显示出改善的胰岛素分泌，胰岛形态和血管化，抗氧化防御系统，以及线粒体生物合成和功能的调节因子。为了了解这种保护的起源，MLSD治疗后11天，在胰腺组织中评估胰岛炎的严重程度和炎症参数，显示胰岛炎和促炎细胞因子肿瘤坏死因子-α的水平显着降低，白细胞介素-1β，和干扰素-γ在MacT3小鼠中。
■结果表明，TIMP3参与维护胰岛结构和功能，至少在某种程度上,通过调节与胰岛炎相关的促炎细胞因子的产生，可能代表了T1DM的一种新的治疗策略。
■多次低剂量链脲佐菌素（MLDS）治疗12周后，在CD68启动子下的骨髓细胞中特异性过度表达TIMP3的糖尿病小鼠（MacT3小鼠）显示出改善的胰岛素分泌，胰岛形态和血管化，抗氧化防御系统，以及线粒体生物合成和功能的调节因子。为了了解这种保护的起源，MLSD治疗后11天，在胰腺组织中评估胰岛炎的严重程度和炎症参数，显示胰岛炎和促炎细胞因子肿瘤坏死因子-α的水平显着降低，白细胞介素-1β，和干扰素-γ在MacT3小鼠中。
■结果表明，TIMP3参与维护胰岛结构和功能，至少在某种程度上,通过调节与胰岛炎相关的促炎细胞因子的产生，可能代表了T1DM的一种新的治疗策略。
