title: 7-Ketocholesterol-induced inflammation signals mostly through the TLR4 receptor both in vitro and in vivo.
abstract: The cholesterol oxide 7-ketocholesterol (7KCh) has been implicated in numerous age-related diseases such as atherosclerosis, Alzheimer's disease, Parkinson's disease, cancer and age-related macular degeneration. It is formed by the autooxidation of cholesterol and especially cholesterol-fatty acid esters found in lipoprotein deposits. This molecule causes complex and potent inflammatory responses in vitro and in vivo. It is suspected of causing chronic inflammation in tissues exposed to oxidized lipoprotein deposits. In this study we have examined the inflammatory pathways activated by 7KCh both in cultured ARPE19 cells and in vivo using 7KCh-containing implants inserted into the anterior chamber of the rat eye. Our results indicate that 7KCh-induced inflammation is mediated mostly though the TLR4 receptor with some cross-activation of EGFR-related pathways. The majority of the cytokine inductions seem to signal via the TRIF/TRAM side of the TLR4 receptor. The MyD88/TIRAP side only significantly effects IL-1β inductions. The 7KCh-induced inflammation also seems to involve a robust ER stress response. However, this response does not seem to involve a calcium efflux-mediated UPR. Instead the ER stress response seems to be mediated by yet identified kinases activated through the TLR4 receptor. Some of the kinases identified are the RSKs which seem to mediate the cytokine inductions and the cell death pathway but do not seem to be involved in the ER stress response.
authors.affiliation: Mechanisms of Retinal Diseases Section, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jiahn-Dar
authors.initials: JD
authors.lastname: Huang
authors.affiliation: Mechanisms of Retinal Diseases Section, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Juan
authors.initials: J
authors.lastname: Amaral
authors.affiliation: Mechanisms of Retinal Diseases Section, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jung Wha
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Mechanisms of Retinal Diseases Section, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ignacio R
authors.initials: IR
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D003521:Cyclopropanes / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D007653:Ketocholesterols / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D002867:Chromones; D003521:Cyclopropanes; D005229:Fatty Acids, Monounsaturated; D058847:Inflammasomes; D007653:Ketocholesterols; D009025:Morpholines; D016328:NF-kappa B; D050826:Suppressor of Cytokine Signaling Proteins; D051197:Toll-Like Receptor 4; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011494:Protein Kinases; C003345:sterculic acid; C003001:7-ketocholesterol