| Oxysterols exert proinflammatory effects in placental trophoblasts via TLR4-dependent, cholesterol-sensitive activation of NF-κB. | |
| | |
MedLine Citation:
|
PMID: 22238372 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
|
Oxidised cholesterol metabolites (oxysterols) promote inflammation in a variety of cell types and are thought to be involved in a number of disease pathologies. Oxysterol concentrations are increased in pregnancy, together with systemic oxidative stress and inflammation. We tested the hypothesis that oxysterols 25-hydroxycholesterol (25-OHC) and 7-ketocholesterol (7-ketoC) promote placental trophoblast inflammation, and determined the mechanisms involved. Treatment of primary trophoblasts in culture with 25-OHC and 7-ketoC increased the production of proinflammatory cytokines (IL-6, MIP-1β and TNF-α) in a concentration-dependent fashion. Inhibition of TLR4 activation using selective inhibitors of TLR4 complex formation (OxPAPC) or signalling transmission (CLI095) prevented lipopolysaccharide (LPS)- and oxysterol-induced inflammatory cytokine production. Pre-treatment of trophoblasts with selective inhibitors of IKK activity (parthenolide and TPCA-1) reduced oxysterol- and LPS-stimulated inflammatory responses, consistent with the involvement of the NF-κB pathway downstream of TLR4 signalling. Both oxysterols also increased the phosphorylation and nuclear localisation of NF-κB subunit p65/RelA. Oxysterols are also known to activate liver X receptors (LXRs) which can inhibit inflammatory signalling, either directly or indirectly via membrane cholesterol reduction. Treatment with the LXR agonist, T0901317, exerted significant anti-inflammatory effects, reducing LPS- and oxysterol-driven cytokine production. Treatment with methyl-β-cyclodextrin to deplete membrane microdomain cholesterol and thereby disrupt TLR4 signalling, similarly abrogated their effects. Together, these findings indicate that although oxysterols likely activate both pro- and anti-inflammatory pathways in the placenta, the predominant effect is the promotion of placental inflammation via TLR4-dependent activation of NF-κB. |
| | |
Authors:
|
Irving L M H Aye; Brendan J Waddell; Peter J Mark; Jeffrey A Keelan |
Publication Detail:
|
Type: JOURNAL ARTICLE Date: 2012-1-10 |
Journal Detail:
|
Title: Molecular human reproduction Volume: - ISSN: 1460-2407 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
|
Created Date: 2012-1-12 Completed Date: - Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 9513710 Medline TA: Mol Hum Reprod Country: - |
Other Details:
|
Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
|
School of Women's and Infants' Health, Faculty of Medicine, Dentistry and Health Sciences. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Association Study of CYP17 and HSD11B1 in Polycystic Ovary Syndrome Utilizing Comprehensive Gene Cov...
Next Document: BC1-FMRP interaction is modulated by 2'-O-methylation: RNA-binding activity of the tudor domain and ...