title: Tumor necrosis factor alpha and adalimumab differentially regulate CD36 expression in human monocytes.
abstract: In chronic inflammatory diseases, such as rheumatoid arthritis, inflammation acts as an independent cardiovascular risk factor and the use of anti-inflammatory drugs, such as anti-tumor necrosis factor alpha (anti-TNFalpha), may decrease this risk. The phagocytosis of oxidized low density lipoproteins (LDLs) accumulated in the subendothelium by mononuclear cells influences atherosclerosis and depends on CD36 expression. We investigated the role of TNFalpha and adalimumab, a human anti-TNFalpha monoclonal antibody widely used in human pathology, in CD36 expression in human monocytes. Human monocytes were prepared by adherence from whole-blood buffy-coat fractions from healthy donors. CD36 expression was assessed by RT-PCR and flow cytometry, with various TNFalpha or adalimumab concentrations. Implication of peroxisome proliferator-activated receptor (PPAR)gamma in the regulation of CD36 expression was assessed using specific inhibitor or gel shift assays. The impact of redox signaling was investigated using quantification of reactive oxygen species, antioxidant and a NADPH oxidase inhibitor. The F(ab')2 fragment of adalimumab was isolated and its effect was analyzed. TNFalpha inhibits both CD36 membrane expression and mRNA expression. This inhibition involves a reduction in PPARgamma activation. In contrast, adalimumab increases both CD36 membrane expression and mRNA expression. This induction is independent of the Fc portion of adalimumab and involves redox signaling via NADPH oxidase activation. CD36 expression on human monocytes is inhibited by TNFalpha and independently increased by adalimumab. These data highlight that pro-inflammatory cytokines and their specific neutralization influence the expression of cellular receptors implicated in atherosclerosis. Further studies are needed to investigate the clinical implications of these results in accelerated atherosclerosis observed in rheumatoid arthritis.
authors.affiliation: EA2405, Université Paul Sabatier, IFR31, BP84225, 31432 Toulouse Cedex 4, France. keltiak@aol.com
authors.forename: Jean Frédéric
authors.initials: JF
authors.lastname: Boyer
authors.forename: Patricia
authors.initials: P
authors.lastname: Balard
authors.forename: Hélène
authors.initials: H
authors.lastname: Authier
authors.forename: Bruno
authors.initials: B
authors.lastname: Faucon
authors.forename: José
authors.initials: J
authors.lastname: Bernad
authors.forename: Bernard
authors.initials: B
authors.lastname: Mazières
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Davignon
authors.forename: Alain
authors.initials: A
authors.lastname: Cantagrel
authors.forename: Bernard
authors.initials: B
authors.lastname: Pipy
authors.forename: Arnaud
authors.initials: A
authors.lastname: Constantin
mesh_terms: D000068879:Adalimumab; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001172:Arthritis, Rheumatoid / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D018955:CD36 Antigens / Q000096:biosynthesis / Q000187:drug effects*; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018955:CD36 Antigens; D007140:Immunoglobulin Fab Fragments; D047495:PPAR gamma; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab