Background and purpose: The pro-inflammatory cytokine, interleukin-1b (IL-1b), has been implicated in the pathogenesis of atherosclerosis, potentially via its release from vascular endothelium. Endothelial cells (EC) synthesize IL-1b in response to inflammatory stimuli, but the demonstration and mechanism of release of IL-1 from ECs remains unclear. In activated monocytes, efficient release of bioactive IL-1b occurred via activation of ATP-gated P2X 7 receptors (P2X 7 Rs). Activation of P2X 7 R in ECs from human umbilical vein (HUVECs) released IL-1 receptor antagonist (IL-1Ra). The purpose of this study was to provide a quantitative investigation of P2XR expression and function, in parallel with IL-1b and IL-1Ra synthesis, processing and release, in HUVECs under pro-inflammatory conditions. Experimental approach: Quantitative RT-PCR, immunoblotting, ELISA, flow cytometry, and whole-cell patch clamp recordings were used to determine protein expression and receptor function. IL-8-luciferase-reporter was used as an IL-1 sensitive bioassay. Key results: HUVECs expressed P2X 4 R and P2X 7 R subtypes and both were significantly up-regulated under inflammatory conditions. P2X 7 R currents were increased 3-fold by inflammatory stimuli, whereas no P2X 4 R-mediated currents were detected. Caspase-1, but not IL-1b, was present intracellularly under basal conditions; inflammatory stimuli activated the synthesis of intracellular pro-IL-1b and increased caspase-1 levels. Activation of P2X 7 Rs resulted in low-level release of bioactive IL-1b and simultaneous release of IL-1Ra. The net biological effect of release was anti-inflammatory. Conclusions and implications: Endothelial P2X 7 Rs induced secretion of both pro-and anti-inflammatory IL-1 receptor ligands, the balance of which may provide a means for altering the inflammatory state of the arterial vessel wall.

Key PointsQuestionIs transcatheter aortic valve implantation (TAVI) noninferior to surgical aortic valve replacement (surgery) in patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk?FindingsIn this randomized clinical trial that included 913 patients at moderately increased operative risk due to age or comorbidity, all-cause mortality at 1 year was 4.6% with TAVI vs 6.6% with surgery, a difference that met the prespecified noninferiority margin of 5%.MeaningAmong patients aged 70 years or older with severe, symptomatic aortic stenosis and moderately increased operative risk, treatment with TAVI was noninferior to surgery with respect to all-cause mortality at 1 year.

IL-1ra was associated with a sustained, significant reduction in neointima after vessel wall injury as long as it is given for the duration of the stimulation of the IL-1 system, in this case at least 28 days. This suggests that therapies based on the antagonism of IL-1 may modulate the coronary artery response to injury.