Abstract
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 1st 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.
Highlights
Healthy pregnancy is characterized by dynamic inflammatory changes throughout gestation
Aberrant PPARγ levels/activity have been associated with human pathologies such as gestational diabetes (GDM), preterm birth and IUGR29,30
Several studies have explored the effects of inflammation on the placenta in rodent and human trophoblast cell models[49,50]
Summary
Healthy pregnancy is characterized by dynamic inflammatory changes throughout gestation. Several pregnancy disorders, including preeclampsia (PE), intrauterine growth restriction (IUGR), and preterm birth (PTB) that are associated with abnormal placental development, often show pathological levels of both local and systemic inflammation[2,3,4] Both PTB and PE placentae have increased pro-inflammatory cytokine release compared to gestational age matched controls[5,6,7,8,9,10]. In-vitro investigation of human term placentae and gestational membranes showed that activation of PPARγ could reduce LPS-induced cytokine expression, supporting its anti-inflammatory action in the human placenta[33] It remains unclear whether the roles of PPARγ in inflammation and trophoblast differentiation are linked. We hypothesized that activation of PPARγ by Rosiglitazone would lessen inflammation-mediated effects on trophoblast differentiation and pathophysiology
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