| First Author | Oberoi R | Year | 2016 |
| Journal | PLoS One | Volume | 11 |
| Issue | 7 | Pages | e0160145 |
| PubMed ID | 27467817 | Mgi Jnum | J:253080 |
| Mgi Id | MGI:6094310 | Doi | 10.1371/journal.pone.0160145 |
| Citation | Oberoi R, et al. (2016) Targeting Tumor Necrosis Factor-alpha with Adalimumab: Effects on Endothelial Activation and Monocyte Adhesion. PLoS One 11(7):e0160145 |
| abstractText | 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)-alpha is known as a crucial mediator of early pro-atherosclerotic events. Epidemiologic data suggest that blockade of TNF-alpha 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-alpha blockade by adalimumab-which is approved for several inflammatory disorders-on endothelial activation and monocyte adhesion under pro-atherosclerotic conditions. METHODS AND 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-alpha. The TNF-alpha 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-alpha 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. CONCLUSION: Our results show that adalimumab prevents major inflammatory effects of TNF-alpha on endothelial activation, endothelial monocyte adhesion, endothelial leakage and therefore extends the therapeutic options of adalimumab to limit vascular inflammation. |
