Abstract
IntroductionTNFα is a proinflammatory cytokine that plays a central role in the pathogenesis of rheumatoid arthritis (RA). We investigated the effects of certolizumab pegol, a TNFα blocker, on endothelial cell function and angiogenesis.MethodsHuman dermal microvascular endothelial cells (HMVECs) were stimulated with TNFα with or without certolizumab pegol. TNFα-induced adhesion molecule expression and angiogenic chemokine secretion were measured by cell surface ELISA and angiogenic chemokine ELISA, respectively. We also examined the effect of certolizumab pegol on TNFα-induced myeloid human promyelocytic leukemia (HL-60) cell adhesion to HMVECs, as well as blood vessels in RA synovial tissue using the Stamper-Woodruff assay. Lastly, we performed HMVEC chemotaxis, and tube formation.ResultsCertolizumab pegol significantly blocked TNFα-induced HMVEC cell surface angiogenic E-selectin, vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression and angiogenic chemokine secretion (P < 0.05). We found that certolizumab pegol significantly inhibited TNFα-induced HL-60 cell adhesion to HMVECs (P < 0.05), and blocked HL-60 cell adhesion to RA synovial tissue vasculature (P < 0.05). TNFα also enhanced HMVEC chemotaxis compared with the negative control group (P < 0.05) and this chemotactic response was significantly reduced by certolizumab pegol (P < 0.05). Certolizumab pegol inhibited TNFα-induced HMVEC tube formation on Matrigel (P < 0.05).ConclusionOur data support the hypothesis that certolizumab pegol inhibits TNFα-dependent leukocyte adhesion and angiogenesis, probably via inhibition of angiogenic adhesion molecule expression and angiogenic chemokine secretion.
Highlights
TNFa is a proinflammatory cytokine that plays a central role in the pathogenesis of rheumatoid arthritis (RA)
Certolizumab pegol inhibits TNFa-induced adhesion molecule expression on human dermal microvascular endothelial cell (HMVEC) Previous studies have demonstrated that HMVECs have increased expression of select adhesion molecules induced by TNFa [28]
Our findings indicated that the peak time for E-selectin expression was 6 hours, whereas that for intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression on HMVECs was 24 hours (Figure 1A to 1C)
Summary
TNFa is a proinflammatory cytokine that plays a central role in the pathogenesis of rheumatoid arthritis (RA). We investigated the effects of certolizumab pegol, a TNFa blocker, on endothelial cell function and angiogenesis. Angiogenesis is integral to many physiological and pathological processes, but is overactive in disease states such as wound healing, tumor growth [1], cardiovascular disease and rheumatoid arthritis (RA) [2]. The onset of angiogenesis depends on the release of proangiogenic mediators that activate endothelial cells (ECs) and initiate their proliferation and migration [3]. Reduction in TNFa improves the signs and symptoms of RA, and the availability of TNFa inhibitors has revolutionized treatment of this illness [18]
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