title: Infliximab reverses suppression of cholesterol efflux proteins by TNF-α: a possible mechanism for modulation of atherogenesis.
abstract: Tumor necrosis factor- (TNF-) α is a proinflammatory proatherogenic cytokine. Infliximab, an anti-TNF-α monoclonal antibody, is effective in treating rheumatoid arthritis. However, its impact on cardiovascular burden and lipid transport is unclear. The present study investigates the effect of TNF-α and infliximab on reverse cholesterol transport (RCT) proteins. Uptake of modified lipoproteins by macrophages in the vasculature leads to atherogenic foam cell formation. RCT is mediated by proteins including ATP binding cassette transporters A1 (ABCA1), G1 (ABCG1), liver X receptor- (LXR-) α, and 27-hydroxylase. RCT counteracts lipid overload by ridding cells of excess cholesterol. THP-1 human monocytes were incubated with either TNF-α alone or TNF-α with infliximab. Expression of proteins involved in cholesterol efflux was analyzed. TNF-α significantly reduced both ABCA1 and LXR-α mRNA (to 68.5 ± 1.59%, P < 0.05, and 41.2 ± 0.25%, P < 0.01, versus control set as 100%, resp.). Infliximab nullified the TNF-α effect. Results were confirmed by Western blot. Infliximab abolished the increase in foam cells induced by TNF-α. TNF-α treatment significantly reduces ABCA1 and LXR-α expression in monocytes, thus bringing about a proatherogenic state. The anti-TNF drug infliximab, commonly used in rheumatology, restored RCT proteins. This is the first report of an atheroprotective effect of infliximab on RCT in monocytes.
authors.affiliation: Winthrop Research Institute and Division of Rheumatology, Allergy and Immunology, Department of Medicine, Winthrop-University Hospital, 222 Station Plaza North, Suite 502, Mineola, NY 11501, USA.
authors.forename: Iryna
authors.identifier: 0000-0001-7508-6337
authors.initials: I
authors.lastname: Voloshyna
authors.affiliation: Winthrop Research Institute and Division of Rheumatology, Allergy and Immunology, Department of Medicine, Winthrop-University Hospital, 222 Station Plaza North, Suite 502, Mineola, NY 11501, USA.
authors.forename: Sangeetha
authors.identifier: 0000-0002-6317-0053
authors.initials: S
authors.lastname: Seshadri
authors.affiliation: Winthrop Research Institute and Division of Rheumatology, Allergy and Immunology, Department of Medicine, Winthrop-University Hospital, 222 Station Plaza North, Suite 502, Mineola, NY 11501, USA.
authors.forename: Kamran
authors.identifier: 0000-0002-6288-3502
authors.initials: K
authors.lastname: Anwar
authors.affiliation: Winthrop Research Institute and Division of Rheumatology, Allergy and Immunology, Department of Medicine, Winthrop-University Hospital, 222 Station Plaza North, Suite 502, Mineola, NY 11501, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Littlefield
authors.affiliation: Winthrop Research Institute and Division of Rheumatology, Allergy and Immunology, Department of Medicine, Winthrop-University Hospital, 222 Station Plaza North, Suite 502, Mineola, NY 11501, USA.
authors.forename: Elise
authors.initials: E
authors.lastname: Belilos
authors.affiliation: Winthrop Research Institute and Division of Rheumatology, Allergy and Immunology, Department of Medicine, Winthrop-University Hospital, 222 Station Plaza North, Suite 502, Mineola, NY 11501, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Carsons
authors.affiliation: Winthrop Research Institute and Division of Rheumatology, Allergy and Immunology, Department of Medicine, Winthrop-University Hospital, 222 Station Plaza North, Suite 502, Mineola, NY 11501, USA.
authors.forename: Allison B
authors.initials: AB
authors.lastname: Reiss
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D050197:Atherosclerosis / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D053493:Cholestanetriol 26-Monooxygenase / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D000069285:Infliximab; D008077:Lipoproteins, LDL / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000911:Antibodies, Monoclonal; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D000069285:Infliximab; D053493:Cholestanetriol 26-Monooxygenase