Liver X Receptor Activation Attenuates Oxysterol-Induced Inflammatory Responses in Fetoplacental Endothelial Cells

by Selleckchem | Jun 11 2023

Oxysterols are oxidized cholesterol derivatives whose systemic levels are found elevated in pregnancy disorders such as gestational diabetes mellitus (GDM). Oxysterols act through various cellular receptors and serve as a key metabolic signal, coordinating inflammation. GDM is a condition of low-grade chronic inflammation accompanied by altered inflammatory profiles in the mother, placenta and fetus. Higher levels of two oxysterols, namely 7-ketocholesterol (7-ketoC) and 7β-hydroxycholesterol (7β-OHC), were observed in fetoplacental endothelial cells (fpEC) and cord blood of GDM offspring. In this study, we tested the effects of 7-ketoC and 7β-OHC on inflammation and investigated the underlying mechanisms involved. Primary fpEC in culture treated with 7-ketoC or 7β-OHC, induced the activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NFκB) signaling, which resulted in the expression of pro-inflammatory cytokines (IL-6, IL-8) and intercellular cell adhesion molecule-1 (ICAM-1). Liver-X receptor (LXR) activation is known to repress inflammation. Treatment with LXR synthetic agonist T0901317 dampened oxysterol-induced inflammatory responses. Probucol, an inhibitor of LXR target gene ATP-binding cassette transporter A-1 (ABCA-1), antagonized the protective effects of T0901317, suggesting a potential involvement of ABCA-1 in LXR-mediated repression of inflammatory signaling in fpEC. TLR-4 inhibitor Tak-242 attenuated pro-inflammatory signaling induced by oxysterols downstream of the TLR-4 inflammatory signaling cascade. Taken together, our findings suggest that 7-ketoC and 7β-OHC contribute to placental inflammation through the activation of TLR-4. Pharmacologic activation of LXR in fpEC decelerates its shift to a pro-inflammatory phenotype in the presence of oxysterols.

Comments:

The study focuses on the role of two specific oxysterols, 7-ketocholesterol (7-ketoC) and 7β-hydroxycholesterol (7β-OHC), in inducing inflammation in the context of gestational diabetes mellitus (GDM). GDM is a condition characterized by low-grade chronic inflammation, and elevated levels of oxysterols have been observed in individuals with GDM.

The researchers investigated the effects of 7-ketoC and 7β-OHC on inflammation and explored the underlying mechanisms involved. They conducted experiments using primary fetoplacental endothelial cells (fpEC) in culture. The results showed that treatment with 7-ketoC or 7β-OHC led to the activation of two important signaling pathways involved in inflammation: mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NFκB) signaling. This activation, in turn, resulted in the expression of pro-inflammatory cytokines (IL-6, IL-8) and intercellular cell adhesion molecule-1 (ICAM-1) in fpEC.

The researchers also investigated the role of liver-X receptor (LXR), which is known to have anti-inflammatory effects. They found that treatment with an LXR synthetic agonist called T0901317 reduced the inflammatory responses induced by oxysterols in fpEC. This suggests that LXR activation can dampen the shift of fpEC towards a pro-inflammatory phenotype in the presence of oxysterols. Additionally, the study implicated ATP-binding cassette transporter A-1 (ABCA-1), an LXR target gene, by showing that an inhibitor of ABCA-1 called Probucol antagonized the protective effects of LXR activation. This suggests that ABCA-1 may be involved in LXR-mediated repression of inflammatory signaling in fpEC.

Furthermore, the study explored the role of Toll-like receptor 4 (TLR-4) in the inflammatory response induced by oxysterols. TLR-4 is a key receptor involved in the inflammatory signaling cascade. The researchers used a TLR-4 inhibitor called Tak-242 and found that it attenuated the pro-inflammatory signaling induced by oxysterols downstream of TLR-4.

In summary, the study demonstrates that 7-ketoC and 7β-OHC contribute to placental inflammation in the context of GDM through the activation of TLR-4. Activation of LXR in fpEC using a synthetic agonist dampened the pro-inflammatory response induced by oxysterols. The involvement of ABCA-1 in this process suggests a potential mechanism for LXR-mediated repression of inflammatory signaling. These findings provide insights into the molecular mechanisms underlying placental inflammation in GDM and highlight potential therapeutic targets for mitigating inflammation in pregnancy disorders.