Thrombin effects on decidual TLR expression
The decidua acts in an immunologically paradoxical fashion (i.e., accepting the semi-allogenic placenta, while maintaining host defenses against an array of microbial pathogens). Placental abruption/decidual hemorrhage is a major cause of perinatal morbidity and mortality and preterm delivery (PTD) and is associated with both aseptic inflammatory responses as well as increased rates of frank chorioamnionitis (CAM). Abruption results in intense decidual thrombin generation and, in severe cases, hypofibrinogenemia and disseminated intra-vascular coagulation. Recurrent abruption is also associated with a 7-fold higher rate of preterm premature rupture of the membranes (PPROM). Our previous studies demonstrated that thrombin, acts via protease activated receptors (PARs) to increase decidual matrix metalloproteinase (MMP) and interleukin-8 (IL-8) expression, factors strongly linked to PPROM. We now reveal that 1) decidualized stromal cells, i.e., decidual cells (DCs) and human endometrial endothelial cells (HEECs) express specific Toll-like Receptors (TLRs) and their intermediate signaling proteins; 2) thrombin alters DC expression of TLR2, TLR3 and TLR4 whereas in HEECs, thrombin alters the expression of several TLR pathway intermediates without affecting TLR gene expression. TLRs recognize and respond to conserved pathogen-associated molecular patterns (PAMPs) expressed by microbes and stress proteins released by dying cells. Activation of TLRs is necessary to promote innate immunity. The underlying hypothesis of this study is that:
- Excess thrombin alters TLR expression and signaling in decidual and endothelial cells.
- Alteration of TLRs increases susceptibility to an ascending genital tract infection leading to an inflammatory reaction that promotes PPROM and/or PTD.
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