Modulation of endothelial function by pro-inflammatory cytokines involved in chronic inflammatory diseases. Focus on IL-17A, IL-20, IL-23 and IL-9

Abstract

Chronic inflammatory diseases (CID) such as rheumatoid arthritis, systemic lupus erythematosus, spondyloarthritis are associated with increased cardiovascular risk secondary to the presence of endothelial dysfunction. In addition to the well-known cytokines (TNF-α, IL-1β and IL-6), emerging data identified new cytokines such as IL-17A, IL-20, IL-23 and IL-9 key-players of the pathogenesis of CID. To date, whether these cytokines might contribute to CID-associated endothelial dysfunction is not known. This study investigated the effect of IL-17A, IL-20, IL-23 and IL-9 on endothelium-dependent relaxation in response to acetylcholine (Ach) in aortic rings from male Lewis rats. Thoracic aortic rings are incubated for 1 or 24 h at 37 °C with 2 concentrations of each cytokine (IL-17A: 250 pg/mL and 10 ng/mL; IL-20: 500 pg/mL and 5 ng/mL; IL-23: 80 pg/mL and 10 ng/mL; and IL-9: 300 pg/mL and 10 ng/mL). Incubation with 10 ng/ml TNF-α was used as a positive control and with vehicle as negative control. At the end of the incubation period, concentration-response curves to Ach (10 −11 –10 −4 mol/L) were assessed. As expected, a 24 h- but not 1 h-incubation with TNF-α reduced Ach-induced relaxation. The same result was obtained with IL-17A (10 ng/mL). By contrast, IL-20 did not change Ach-induced relaxation whatever the concentration and the incubation time. Impairment in vascular relaxation was observed after exposure to IL-9 (10 ng/mL), both after 1 h- and more severely after 24 h-incubation. As regards IL-23, an effect was observed only after 1 h incubation and with high concentration. Our data demonstrated that IL-17A, IL-23 and IL-9 but not IL-20 induced endothelial dysfunction, with different kinetics profiles. IL-9 exhibited the most important effect thus revealing a new putative role of this pleiotropic cytokine in CID-associated cardiovascular risk. Further studies are needed to confirm these data on animal models of diseases.