The role of tumor necrosis factor in triggering activation of natural killer cell, multi-organ mitochondrial dysfunction and hypertension during pregnancy

Pre-eclampsia (PE) is a hypertensive disorder of pregnancy associated with chronic inflammation, mitochondrial (mt) dysfunction and fetal demise. Natural Killer cells (NK cells) are critical for the innate immune response against tumors or infection by disrupting cellular mt function and causing cell death. Although NK cells can be stimulated by Tumor necrosis factor alpha (TNF-alpha), we don't know the role of TNF-alpha on NK cell mediated mt dysfunction during PE. Our objective was to determine if mechanisms of TNF-alpha induced hypertension included activation of NK cells and multi-organ mt dysfunction during pregnancy. Pregnant rats were divided into 2 groups: normal pregnant (NP) (n = 18) and NP + TNF-alpha (n = 18). On gestational day 14, TNF-alpha (50 ng/ml) was infused via mini-osmotic pump and on day 18, carotid artery catheters were inserted. Blood pressure (MAP) and samples were collected on day 19. TNF-alpha increased MAP (109 +/- 2 vs 100 +/- 2, p < 0.05), circulating cytolytic NK cells (0.771 +/- 0.328 vs.0.008 +/- 0.003% gated, <0.05) and fetal reabsorptions compared to NP rats. Moreover, TNF-alpha caused mtROS in the placenta (12976 +/- 7038 vs 176.9 +/- 68.04% fold, p < 0.05) and in the kidney (2191 +/- 1027 vs 816 +/- 454.7% fold, p < 0.05) compared to NP rats. TNF-alpha induced hypertension is associated fetal demise, activation of NK cells and multi-organ mt dysfunction which could be mechanisms for fetal demise and hypertension. Understanding of the mechanisms by which TNF-alpha causes pathology is important for the use of anti-TNF-alpha therapeutic agents in pregnancies complicated by PE.

Automated summary

TNF-alpha may induce hypertension during pregnancy by activating NK cells and causing multi-organ mitochondrial dysfunction.