Liver X Receptor Activation Attenuates Oxysterol-Induced Inflammatory Responses in Fetoplacental Endothelial Cells
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-gra...
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MDPI AG
2023-04-01
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| author | Meekha George Magdalena Lang Chaitanya Chakravarthi Gali Joshua Adekunle Babalola Carmen Tam-Amersdorfer Anika Stracke Herbert Strobl Robert Zimmermann Ute Panzenboeck Christian Wadsack |
| author_facet | Meekha George Magdalena Lang Chaitanya Chakravarthi Gali Joshua Adekunle Babalola Carmen Tam-Amersdorfer Anika Stracke Herbert Strobl Robert Zimmermann Ute Panzenboeck Christian Wadsack |
| author_sort | Meekha George |
| collection | DOAJ |
| description | 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. |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T05:09:19Z |
| publishDate | 2023-04-01 |
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| spelling | doaj.art-a5f735ac4f3546cc84246a90c443a31f2023-11-17T18:43:42ZengMDPI AGCells2073-44092023-04-01128118610.3390/cells12081186Liver X Receptor Activation Attenuates Oxysterol-Induced Inflammatory Responses in Fetoplacental Endothelial CellsMeekha George0Magdalena Lang1Chaitanya Chakravarthi Gali2Joshua Adekunle Babalola3Carmen Tam-Amersdorfer4Anika Stracke5Herbert Strobl6Robert Zimmermann7Ute Panzenboeck8Christian Wadsack9Department of Obstetrics and Gynecology, Medical University of Graz, 8036 Graz, AustriaOtto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology, Medical University of Graz, 8010 Graz, AustriaMy Pura Vida Wellness Private Limited, Hyderabad 500081, IndiaDiagnostics & Research Institute of Pathology, Medical University of Graz, 8010 Graz, AustriaOtto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology, Medical University of Graz, 8010 Graz, AustriaOtto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology, Medical University of Graz, 8010 Graz, AustriaOtto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology, Medical University of Graz, 8010 Graz, AustriaInstitute for Molecular Biosciences, University of Graz, 8010 Graz, AustriaOtto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Immunology, Medical University of Graz, 8010 Graz, AustriaDepartment of Obstetrics and Gynecology, Medical University of Graz, 8036 Graz, AustriaOxysterols 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.https://www.mdpi.com/2073-4409/12/8/1186oxysterolsliver X receptorsATP-binding cassette transporter 1toll-like receptor 4placentaendothelial cells |
| spellingShingle | Meekha George Magdalena Lang Chaitanya Chakravarthi Gali Joshua Adekunle Babalola Carmen Tam-Amersdorfer Anika Stracke Herbert Strobl Robert Zimmermann Ute Panzenboeck Christian Wadsack Liver X Receptor Activation Attenuates Oxysterol-Induced Inflammatory Responses in Fetoplacental Endothelial Cells Cells oxysterols liver X receptors ATP-binding cassette transporter 1 toll-like receptor 4 placenta endothelial cells |
| title | Liver X Receptor Activation Attenuates Oxysterol-Induced Inflammatory Responses in Fetoplacental Endothelial Cells |
| title_full | Liver X Receptor Activation Attenuates Oxysterol-Induced Inflammatory Responses in Fetoplacental Endothelial Cells |
| title_fullStr | Liver X Receptor Activation Attenuates Oxysterol-Induced Inflammatory Responses in Fetoplacental Endothelial Cells |
| title_full_unstemmed | Liver X Receptor Activation Attenuates Oxysterol-Induced Inflammatory Responses in Fetoplacental Endothelial Cells |
| title_short | Liver X Receptor Activation Attenuates Oxysterol-Induced Inflammatory Responses in Fetoplacental Endothelial Cells |
| title_sort | liver x receptor activation attenuates oxysterol induced inflammatory responses in fetoplacental endothelial cells |
| topic | oxysterols liver X receptors ATP-binding cassette transporter 1 toll-like receptor 4 placenta endothelial cells |
| url | https://www.mdpi.com/2073-4409/12/8/1186 |
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