title: Targeting Tumor Necrosis Factor-α with Adalimumab: Effects on Endothelial Activation and Monocyte Adhesion.
abstract: OBJECTIVE
  It is well known that atherosclerotic inflammatory vascular disease is critically driven by oxidized lipids and cytokines. In this regard, tumor necrosis factor (TNF)-α is known as a crucial mediator of early pro-atherosclerotic events. Epidemiologic data suggest that blockade of TNF-α has beneficial effects on vascular outcomes in patients with rheumatoid arthritis, however, detailed mechanistic studies are still lacking. This study aims to elucidate effects of TNF-α blockade by adalimumab-which is approved for several inflammatory disorders-on endothelial activation and monocyte adhesion under pro-atherosclerotic conditions.
  
  
  RESULTS
  Phorbol myristate acetate (PMA) differentiated THP-1 macrophages were stimulated with oxidized low density lipoprotein and subsequent analysis of this conditioned media (oxLDL CM) revealed a strong release of TNF-α. The TNF-α rich supernatant led to activation of human umbilical vein endothelial cells (HUVEC) as shown by enhanced expression of major adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin which was suppressed by the TNF-α inhibitor adalimumab. Accordingly, adalimumab effectively prevented THP-1 monocyte adhesion to endothelial cells under static as well as under flow conditions. Furthermore, adalimumab suppressed endothelial leakage as shown by Evan's blue diffusion across a confluent endothelial monolayer. Of note, after intraperitoneal injection we detected abundant deposition of fluorophore-labelled adalimumab in atherosclerotic plaques of hypercholesterolemic mice.
  
  
  CONCLUSIONS
  Our results show that adalimumab prevents major inflammatory effects of TNF-α on endothelial activation, endothelial monocyte adhesion, endothelial leakage and therefore extends the therapeutic options of adalimumab to limit vascular inflammation.
authors.affiliation: Department of Cardiology and Angiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Raghav
authors.initials: R
authors.lastname: Oberoi
authors.affiliation: Department of Cardiology and Angiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Schuett
authors.affiliation: Department of Cardiology and Angiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Schuett
authors.affiliation: Department of Cardiology and Angiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Koch
authors.affiliation: Department of Cardiology and Angiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Luchtefeld
authors.affiliation: Department of Cardiology and Angiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Grote
authors.affiliation: Department of Cardiology and Angiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schieffer
mesh_terms: D000068879:Adalimumab / Q000494:pharmacology*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects*; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D008077:Lipoproteins, LDL; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D000068879:Adalimumab