The α and β isoforms of IL-1 have differential effects on atherosclerosis, according to new experimental data. These findings are important to consider when selecting anti-inflammatory therapies for patients with cardiovascular disease and are particularly relevant in the context of the CANTOS trial.

During early atherogenesis in Apoe–/– mice fed a Western diet, treatment with monoclonal antibodies against IL-1α or against both IL-1 isoforms decreased atherosclerotic lesion area and compensatory outward remodelling in the aortic root, whereas antibodies against IL-1β did not impair outward vessel remodelling. In hypercholesterolaemic Apoe–/– mice with established atherosclerosis, selective IL-1β neutralization promoted a shift in circulating monocytes to a less inflammatory state, increased the levels of circulating IL-10 (an anti-inflammatory cytokine) and decreased the area of established atheromata in the aortic root, without limiting outward vessel remodelling. By contrast, IL-1α neutralization had no significant effect on established atheromata. These findings indicate that IL-1α is involved in early atherogenesis, whereas IL-1β drives inflammation during the evolution of advanced atheroma.

The investigators suggest that the observed differences might arise from distinct signalling mechanisms of the two isoforms. IL-1α is mainly associated with the cell membrane and operates via juxtacrine signalling, whereas IL-1β is released and acts through paracrine and endocrine signalling.

IL-1 signalling can be inhibited clinically with the use of canakinumab (a monoclonal antibody against IL-1β) or anakinra (an antagonist of the IL-1 receptor that blocks the action of both IL-1 isoforms), and an antibody against IL-1α has undergone clinical testing. Moreover, the CANTOS trial showed that canakinumab reduced recurrent cardiovascular events in patients with myocardial infarction who had residual inflammatory risk. The current experimental findings help to interpret the CANTOS trial and to guide anti-inflammatory interventions in patients with cardiovascular disease.