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Inflammatory processes accompany M\u03d5 foam cell formation in the artery wall, yet the relationship between M\u03d5 lipid loading and their response to inflammatory stimuli remains elusive. We investigated proinflammatory gene expression in thioglycollate-elicited peritoneal M\u03d5s, bone marrow\u2013derived M\u03d5s and dendritic cells, and RAW264.7 cells. Loading with oxLDL did not induce peritoneal M\u03d5 apoptosis or modulate basal-level expression of proinflammatory genes. Upon stimulation of TLR4, the rapid induction of IFN-\u03b2 was inhibited in cells loaded with oxLDL, whereas the induction of other proinflammatory genes by TLR4 (LPS), TLR3 (polyriboinosinic-polyribocytidylic acid), TLR2 (Pam3CSK4), and TLR9 (CpG) remained comparable within the first 2 h. Subsequently, the expression of a subset of proinflammatory genes (e.g., IL-1\u03b2, IL-6, CCL5) was reduced in oxLDL-loaded cells at the level of transcription. This phenomenon was partially dependent on NF erythroid 2\u2013related factor 2 (NRF2) but not on nuclear liver X receptors \u03b1 and \u03b2 (LXR\u03b1,\u03b2), peroxisome proliferator-activated receptor-\u03b3 (PPAR\u03b3), and activating transcription factor 3 (ATF3). LPS-induced NF-\u03baB reporter activity and intracellular signaling by NF-\u03baB and MAPK pathways were comparable in oxLDL-loaded M\u03d5s, yet the binding of p65\/RelA (the prototypic NF-\u03baB family member) was reduced at IL-6 and CCL5 promoters. This study revealed that oxLDL loading of M\u03d5s negatively regulates transcription at late stages of TLR-induced proinflammatory gene expression and implicates epigenetic mechanisms such as histone deacetylase activity.<\/jats:p>","DOI":"10.4049\/jimmunol.1601363","type":"journal-article","created":{"date-parts":[[2017,8,8]],"date-time":"2017-08-08T00:30:25Z","timestamp":1502152225000},"page":"2149-2157","source":"Crossref","is-referenced-by-count":46,"title":["Oxidized Low-Density Lipoprotein Loading of Macrophages Downregulates TLR-Induced Proinflammatory Responses in a Gene-Specific and Temporal Manner through Transcriptional Control"],"prefix":"10.1093","volume":"199","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2174-2217","authenticated-orcid":false,"given":"Jenny","family":"Jongstra-Bilen","sequence":"first","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network , Toronto, Ontario M5G 1L7,","place":["Canada"]},{"name":"Department 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1A8,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6915-9018","authenticated-orcid":false,"given":"Mengyi K","family":"Li","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network , Toronto, Ontario M5G 1L7,","place":["Canada"]},{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha","family":"White-Alfred","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network , Toronto, Ontario M5G 1L7,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5637-8569","authenticated-orcid":false,"given":"Ragave","family":"Ilaalagan","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network , Toronto, Ontario M5G 1L7,","place":["Canada"]},{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0483-5529","authenticated-orcid":false,"given":"Dario M","family":"Ferri","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network , Toronto, Ontario M5G 1L7,","place":["Canada"]},{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9519-2222","authenticated-orcid":false,"given":"Ashley","family":"Deonarain","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network , Toronto, Ontario M5G 1L7,","place":["Canada"]},{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark H","family":"Wan","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network , Toronto, Ontario M5G 1L7,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharon J","family":"Hyduk","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network , Toronto, Ontario M5G 1L7,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7603-6577","authenticated-orcid":false,"given":"Carolyn L","family":"Cummins","sequence":"additional","affiliation":[{"name":"Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Ontario M5S 3M2,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1696-2867","authenticated-orcid":false,"given":"Myron I","family":"Cybulsky","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network , Toronto, Ontario M5G 1L7,","place":["Canada"]},{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]},{"name":"Department of Immunology, University of Toronto , Toronto, Ontario M5S 1A8,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2017,9,15]]},"reference":[{"key":"2025030614312184300_r1","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1161\/hc0902.104353","article-title":"Inflammation and 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