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

Abstract

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.

Total Flavonoids of Rhizoma Drynariae Treat Osteoarthritis by Inhibiting Arachidonic Acid Metabolites Through AMPK/NFκB Pathway

“…48 Upon entry into the nucleus, NFκB p65•NFκB p55 is phosphorylated and activated, binding to specific DNA sequences to stimulate transcription of relevant inflammatory mediators, including COX-2. 49 In vitro experiments, we stimulated chondrocytes with IL-1β to establish OA model. Results showed that the mRNA and protein contents of COX-2 in chondrocytes significantly increased after IL-1β stimulation, while IKB-α decreased, the phosphorylation level of NFκB p65 increased in chondrocytes, and NFκB p65 increased in the nucleus, suggesting the abnormal activation of NFκB pathway.…”

“… 48 Upon entry into the nucleus, NFκB p65·NFκB p55 is phosphorylated and activated, binding to specific DNA sequences to stimulate transcription of relevant inflammatory mediators, including COX-2. 49 …”