TNFalpha in the Pathogenesis of Diabetes-Induced Embryopathies: Functions and Targets

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Abstract
The Review of Diabetic Studies,2007,4,4,200-208.
Published:February 2008
Type:Editorial
Authors:
Author(s) affiliations:

Arkady Torchinsky and Vladimir Toder

Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Abstract:

Hyperglycemia-induced increase in the production of reactive oxygen species (ROS) is proposed to be an initial step in the pathogenesis of diabetes-induced spontaneous abortions and structural inborn anomalies. However, the subsequent steps in this process are incompletely understood. One of the key molecules involved is tumor necrosis factor-alpha (TNFα): its expression is regulated by ROS and it regulates ROS production in turn. This cytokine has been the focus of many studies addressing the mechanisms of different forms of diabetes-induced embryopathies, such as early pregnancy loss, inborn anomalies, fetal growth retardation as well as some pathologies appearing during adult life. In this review, we analyze the results of these studies and discuss how TNFα may regulate the response of pre- and postimplantation stage embryos to diabetes-induced detrimental stimuli. The data presented in this review suggest that TNFα may play a dual role in the pathogenesis of diabetes-induced embryopathies. It may act both as a mediator of diabetesinduced embryotoxic stimuli leading to the death of periimplantation stage embryos and, possibly, as a suppressor of diabetes-induced apoptosis in post-implantation stage embryos. It also appears that TNFα fulfills these functions via interaction with leukemia inhibitory factor (LIF) and the transcription factor NF-κB. These molecules are presently considered as attractive targets for the treatment of diabetesinduced complications. Therefore, further studies addressing their role in the mechanisms underlying diabetes-induced embryopathies are needed to evaluate the safety of such therapies for diabetic women of childbearing age.