TNFalpha in the pathogenesis of diabetes-induced embryopathies: functions and targets

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 (TNFalpha): 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 TNFalpha may regulate the response of pre- and post-implantation stage embryos to diabetes-induced detrimental stimuli. The data presented in this review suggest that TNFalpha may play a dual role in the pathogenesis of diabetes-induced embryopathies. It may act both as a mediator of diabetes-induced embryotoxic stimuli leading to the death of peri-implantation stage embryos and, possibly, as a suppressor of diabetes-induced apoptosis in post-implantation stage embryos. It also appears that TNFalpha fulfills these functions via interaction with leukemia inhibitory factor (LIF) and the transcription factor NF-kappaB. These molecules are presently considered as attractive targets for the treatment of diabetes-induced 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.

Figure 1

A model of a pathway triggered by TNFα in the uterus of diabetic mice, which can lead to the death of peri-implantation embryos. Diabetes increases TNFα expression and activates NF-κB in the uterus. These effects may be boosted via a positive feedback loop between these molecules and followed by TNFα- and/or NF-κB-induced dysregulation of molecules, such as LIF, LIFR and STAT-3, which have a critical function for uterine receptivity.