Tumor necrosis factor alpha pathways develops liver apoptosis in type 1 diabetes mellitus

INGARAMO PI; RONCO MT; FRANCÉS D E; MONTI J A; PISANI, GERARDO BRUNO; CEBALLOS M P; GALLEANO M; CARRILLO M C; CARNOVALE C E

MOLECULAR IMMUNOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2011 vol. 48 p. 1397 - 1407

0161-5890

We analyzed the contribution of TNF-alfa 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-alfa/TNF-R1, and led to the activation of caspase-8, of nuclear factor kappa B (NFkB), and JNK signaling pathways. The activation of NFkB 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-alfa 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-alfa in the liver, which may be a fundamental key leading to apoptotic cell death, through activation of caspase-8, NFkB and JNK pathways.