Suppression of endothelial cell activity by inhibition of tumor necrosis factor-alpha

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.

The pathogenic role of angiogenesis in rheumatoid arthritis

“…In contrast, TNF non-responders had a markedly elevated number of circulating TH-17 cells and serum IL-17 levels suggesting that TNF is important for TH-17 cells differentiation in RA [64]. Others have shown that TNF can impact RA angiogenesis by modulating endothelial cell secretion of pro-angiogenic adhesion molecules (E-selectin, ICAM1 and VCAM1) and chemokines (CXCL1, CXCL5, CXCL8, CCL2 and CCL5) [65,63]. …”

Soluble molecules of immunoglobulins superfamily in rheumatoid arthritis

“…In RA hyperexpression of ICAM-1 and VCAM-1 on endotheliocytes, macrophages and fibroblasts, provided by the stimulation of pro-inflammatory cytokines, favors chronisation of inflammatory reaction in joint tissues [8,20].…”

Joint Ultrasonography in Rheumatoid Arthritis: Pathogenetic Rationale, Possible Use in Diagnosis, Therapy Efficiency Evaluation, and Outcome Prediction

“…1 представлены основные эффекты цитокинов, участвующих в развитии РА. Провоспалительные цитоки-ны, секретируемые макрофагами (ФНОα, ИЛ1, ИЛ6, ИЛ8, ИЛ18 и фактор, ингибирующий миграцию макрофа-гов), играют центральную роль в ангиогенезе при РА как за счет прямого влияния на эндотелиальные клетки, так и опосредованно, стимулируя выработку проангиогенных факторов различными типами клеток синовиальной обо-лочки [7,[10][11][12][13].…”

“…Процессы неоангиогенеза неразрывно связаны с вос-палением при РА, и наличие этой связи доказано во мно-гих исследованиях [8][9][10][11][12]. Учитывая ведущую роль этих патогенетических механизмов, проводились работы, по-священные изучению связи провоспалительных цитоки-нов и маркеров ангиогенеза [16], с УЗ-признаками, харак-теризующими состояние синовиальной оболочки при РА (табл.…”