Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
George, M; Lang, M; Gali, CC; Babalola, JA; Tam-Amersdorfer, C; Stracke, A; Strobl, H; Zimmermann, R; Panzenboeck, U; Wadsack, C.
Liver X Receptor Activation Attenuates Oxysterol-Induced Inflammatory Responses in Fetoplacental Endothelial Cells.
CELLS-BASEL. 2023; 12(8): 1186
Doi: 10.3390/cells12081186
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- Führende Autor*innen der Med Uni Graz
- George Meekha
- Wadsack Christian
- Co-Autor*innen der Med Uni Graz
- Babalola Joshua Adekunle
- Gali Chaitanya Chakravarthi
- Lang Magdalena
- Panzenboeck Ute
- Stracke Anika
- Strobl Herbert
- Tam-Amersdorfer Carmen
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Humans - administration & dosage
- Female - administration & dosage
- Pregnancy - administration & dosage
- Oxysterols - pharmacology, metabolism
- Liver X Receptors - metabolism
- Endothelial Cells - metabolism
- Toll-Like Receptor 4 - metabolism
- Placenta - metabolism
- Diabetes, Gestational - metabolism
- Inflammation - metabolism
- Find related publications in this database (Keywords)
- oxysterols
- liver X receptors
- ATP-binding cassette transporter 1
- toll-like receptor 4
- placenta
- endothelial cells