Department of Biochemical, Physiological and Nutritional Sciences, University of Messina, Policlinico Universitario, 98125, Messina, Italy.
Amino Acids. 2010 Nov;39(5):1427-33. doi: 10.1007/s00726-010-0605-4. Epub 2010 May 1.
The aberrant expression and activation of transglutaminase 2 (TG2), the ubiquitous enzyme which catalyzes calcium-dependent protein cross-linking reactions, has been reported in many inflammatory diseases. Chronic inflammation, mediated by prolonged activation of brain-resident immunocompetent cells, appears to be involved in the pathogenesis of several age-related diseases, such as Alzheimer's disease. Given that increased TG2 expression has been observed in AD brains, this study was aimed to characterize the role of TG2 in THP-1 monocytes stimulated with amyloid-beta (Aβ). Aβ1-42 treatment dose-dependently increased TG2 expression in THP-1 cells. In particular, a fivefold up-regulation of TG2, compared with control cells, was observed in the presence of 0.5 μM Aβ1-42. At the same concentration, Aβ1-42 was able to promote monocyte maturation as suggested by increased expression of the cell surface antigen CD14 as well as the adhesion-promoting factor fibronectin. The stimulation of THP-1 cells with Aβ1-42 also led to a significant up-regulation of tumor necrosis factor α (TNF-α) and matrix metalloproteinase 9 (MMP-9). Interestingly, THP-1 cell transfection with small interfering RNA directed against TG2 was able to reduce Aβ1-42 increased levels of all the examined markers of monocyte maturation (CD14, fibronectin), and activation (TNF-α, MMP-9). These results indicate that TG2 up-regulation is required for the functional THP-1 monocyte activation induced by Aβ1-42. This work suggests that TG2 inhibition may represent a therapeutic target to ameliorate the inflammation and progression in Alzheimer's disease.
转谷氨酰胺酶 2（TG2）是一种广泛存在的酶，能够催化钙离子依赖的蛋白交联反应，其表达和激活异常与许多炎症性疾病有关。慢性炎症是由脑内免疫活性细胞的长期激活介导的，似乎与几种与年龄相关的疾病的发病机制有关，如阿尔茨海默病。鉴于 AD 脑中观察到 TG2 表达增加，本研究旨在研究 TG2 在淀粉样蛋白-β（Aβ）刺激的 THP-1 单核细胞中的作用。Aβ1-42 处理剂量依赖性地增加了 THP-1 细胞中 TG2 的表达。特别是，与对照细胞相比，在存在 0.5 μM Aβ1-42 的情况下，TG2 的上调了五倍。在相同浓度下，Aβ1-42 能够促进单核细胞成熟，如细胞表面抗原 CD14 以及促进黏附的纤维连接蛋白的表达增加所表明的那样。Aβ1-42 刺激 THP-1 细胞也导致肿瘤坏死因子-α（TNF-α）和基质金属蛋白酶 9（MMP-9）的显著上调。有趣的是，用针对 TG2 的小干扰 RNA 转染 THP-1 细胞能够降低 Aβ1-42 增加的所有单核细胞成熟标志物（CD14、纤维连接蛋白）和激活标志物（TNF-α、MMP-9）的水平。这些结果表明，TG2 的上调是 Aβ1-42 诱导的功能性 THP-1 单核细胞激活所必需的。这项工作表明，TG2 抑制可能代表一种治疗靶点，以改善阿尔茨海默病中的炎症和进展。
