Rosiglitazone blocks first trimester in-vitro placental injury caused by NF-κB-mediated inflammation

Increased inflammation and abnormal placentation are common features of a wide spectrum of pregnancy-related disorders such as intra uterine growth restriction, preeclampsia and preterm birth. The inflammatory response of the human placenta has been mostly investigated in relation to cytokine release, but the direct molecular consequences on trophoblast differentiation have not been investigated. This study measured the general effects of LPS on both extravillous and villous trophoblast physiology, and the involvement of the transcription factors PPARγ and NF-κB, specifically using 1(st) trimester explants and HTR-8/ SVneo cell line models. While both proteins are known for their roles in inflammatory pathways, PPARγ has been identified as an important molecule in trophoblast differentiation, suggesting its potential role in mediating a crosstalk between inflammation and trophoblast differentiation. Here, LPS (1 µg/ml) exposure of first trimester placental villous explants resulted in secretion of inflammatory cytokines, induction of apoptosis and reduction in trophoblast cell proliferation. Additionally, LPS significantly reduced expression of the trophoblast differentiation proteins GCM1 and β-hCG, and increased invasion of the extravillous trophoblast. Activation of PPARγ by Rosiglitazone (10 µM) reversed the LPS-mediated effects on inflammatory cytokine release, trophoblast apoptosis and proliferation compared to controls. Lastly, markers of trophoblast differentiation and invasion reverted to control levels upon activation of PPARγ and concomitant inhibition of NF-κB (either by Rosiglitazone or NF-κB specific inhibitor), revealing a new role for NF-κB in trophoblast invasion. This study reveals a novel PPARγ - NF-κB axis that coordinates inflammatory and differentiation pathways in the human placenta. The ability to reverse trophoblast-associated inflammation with Rosiglitazone offers promise that the PPARγ – NF-κB pathway could one day provide a therapeutic target for placental dysfunction associated with both inflammation and abnormal trophoblast differentiation.