Institute of Experimental Physiology (CONICET), Faculty of Biochemical and Pharmaceutical Sciences (National University of Rosario), Rosario, Argentina.
Mol Immunol. 2011 Jul;48(12-13):1397-407. doi: 10.1016/j.molimm.2011.03.015. Epub 2011 Apr 9.
We analyzed the contribution of TNF-α intracellular pathway in the development of apoptosis in the liver of streptozotocin-induced diabetic rats. In liver tissue, diabetes promoted a significant increase of TNF-α/TNF-R1, and led to the activation of caspase-8, of nuclear factor kappa B (NFκB), and JNK signaling pathways. The activation of NFκB led to an induction of iNOS and consequent increase in NO production. As a consequence of such changes a significant increase of caspase-3 activity and of apoptotic index were observed in the liver of diabetic animals. Importantly, the treatment in vivo of diabetic rats with etanercept (TNF-α blocking antibody) or aminoguanidine (selective iNOS inhibitor) significantly attenuated the induction of apoptosis by reduction of caspase-3 activity. Overall, we demonstrated that in the diabetes enhances TNF-α in the liver, which may be a fundamental key leading to apoptotic cell death, through activation of caspase-8, NFκB and JNK pathways.
我们分析了 TNF-α 细胞内途径在链脲佐菌素诱导的糖尿病大鼠肝凋亡发展中的作用。在肝组织中，糖尿病显著促进了 TNF-α/TNF-R1 的增加，并导致了 caspase-8、核因子 kappa B（NFκB）和 JNK 信号通路的激活。NFκB 的激活导致诱导型一氧化氮合酶（iNOS）的产生，进而导致 NO 产生增加。由于这些变化，糖尿病动物肝脏中 caspase-3 活性和凋亡指数显著增加。重要的是，体内用依那西普（TNF-α 阻断抗体）或氨基胍（选择性 iNOS 抑制剂）治疗糖尿病大鼠，通过降低 caspase-3 活性显著减弱了诱导的凋亡。总的来说，我们证明了在糖尿病中，肝脏中 TNF-α 的增加可能是通过激活 caspase-8、NFκB 和 JNK 途径导致凋亡细胞死亡的关键因素。
