Abstract
Accumulating evidence has shown that preeclampsia (PE) was associated with an aberrant maternal-fetal inflammatory response. In the present study, we first found that in human PE placentas levels of toll-like receptor 4 (TLR4), phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) and inflammatory cytokines IL-6 and MCP-1 were significantly upregulated. Next, we demonstrated a notable increase in systolic blood pressure (SBP) and proteinuria in lipopolysaccharide (LPS)-treated pregnant rats and concomitant high levels of TLR4 and p-p38 in these PE-like rat placentas, which led to aberrant overexpression of both IL-6 and MCP-1, as well as deficient trophoblast invasion and spiral artery (SA) remodeling, and these abnormalities were ameliorated by SB203580, a reported inhibitor of p38. In vitro we further confirmed that LPS triggered the activation of TLR4/p38 signaling pathway, which promoted trophoblast apoptosis and damaged trophoblastic invasion via downstream effectors IL-6 and MCP-1; these mutations were rectified by silencing this signaling pathway. These findings elaborated potential mechanisms that aberrant TLR4/p38 signaling might contribute to PE and LPS-induced PE-like symptom by damaging trophoblast invasion and SA remodeling via activating inflammatory cytokines including IL-6 and MCP-1.
Highlights
Characterized by hypertension and proteinuria, PE is a complex multi-system disease of unknown origin, with potentially life-threatening consequences for both mother and baby (Pauli and Repke, 2015)
Immunohistochemistry showed that toll-like receptor 4 (TLR4) was mainly detected in the cytoplasm of trophoblasts in both normal and preeclamptic placentas; and increased staining of TLR4 was shown in PE (Figure 1A)
We showed TLR4 and p-p38 protein levels were markedly increased in PE placentas, compared with normal gestational placentas (*p < 0.01 vs. normal pregnancy (NP)) (Figures 1B,C)
Summary
Characterized by hypertension and proteinuria, PE is a complex multi-system disease of unknown origin, with potentially life-threatening consequences for both mother and baby (Pauli and Repke, 2015). Toll-like receptors (TLRs) were originally recognized as a central regulator of embryogenesis in Drosophila, and key components of the innate immune system expressed on various immune cells, such as dendritic cells (DCs) (Beg, 2002; Panda et al, 2012). TLR4 was first known to induce expression of genes involved in inflammatory responses (Beg, 2002) and in the first line of defense of the innate inflammatory immune system at the maternal-fetal interface. TLR4 was abundantly expressed in the placentas of the patients who suffer from PE, suggesting a critical role in inflammation-induced abnormal placentation and development (Koga and Mor, 2010; Bernardi et al, 2012; Panda et al, 2012). Characterizing the potential role of TLR4 in PE is of great importance
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