title: Oxidatively modified low density lipoprotein (LDL) inhibits TLR2 and TLR4 cytokine responses in human monocytes but not in macrophages.
abstract: Inflammation characterized by the expression and release of cytokines and chemokines is implicated in the development and progression of atherosclerosis. Oxidatively modified low density lipoproteins, central to the formation of atherosclerotic plaques, have been reported to signal through Toll-like receptors (TLRs), TLR4 and TLR2, in concert with scavenger receptors to regulate the inflammatory microenvironment in atherosclerosis. This study evaluates the role of low density lipoproteins (LDL) and oxidatively modified LDL (oxmLDL) in the expression and release of proinflammatory mediators IκBζ, IL-6, IL-1β, TNFα, and IL-8 in human monocytes and macrophages. Although standard LDL preparations induced IκBζ along with IL-6 and IL-8 production, this inflammatory effect was eliminated when LDL was isolated under endotoxin-restricted conditions. However, when added with TLR4 and TLR2 ligands, this low endotoxin preparation of oxmLDL suppressed the expression and release of IL-1β, IL-6, and TNFα but surprisingly spared IL-8 production. The suppressive effect of oxmLDL was specific to monocytes as it did not inhibit LPS-induced proinflammatory cytokines in human macrophages. Thus, TLR ligand contamination of LDL/oxmLDL preparations can complicate interpretations of inflammatory responses to these modified lipoproteins. In contrast to providing a proinflammatory function, oxmLDL suppresses the expression and release of selected proinflammatory mediators.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
authors.forename: Yashaswini
authors.initials: Y
authors.lastname: Kannan
authors.forename: Kruthika
authors.initials: K
authors.lastname: Sundaram
authors.forename: Chandrakala
authors.initials: C
authors.lastname: Aluganti Narasimhulu
authors.forename: Sampath
authors.initials: S
authors.lastname: Parthasarathy
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wewers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D018955:CD36 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins; D015151:Immunoblotting; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018955:CD36 Antigens; D016207:Cytokines; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D055666:Lipopeptides; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; C417234:NFKBIZ protein, human; D009687:Nuclear Proteins; C508075:Pam(3)CSK(4) peptide; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein