Acid-dependent Interleukin-1 (IL-1) Cleavage Limits Available Pro-IL-1β for Caspase-1 Cleavage

Noncommunicable diseases such as cardiovascular disease (stroke and heart attack), cancer, chronic respiratory disease, and diabetes are a leading cause of death and disability worldwide and are worsened by inflammation. IL-1 is a driver of inflammation and implicated in many noncommunicable diseases. Acidosis is also a key feature of the inflammatory microenvironment; therefore it is vital to explore IL-1 signaling under acidic conditions. A HEK-IL-1 reporter assay and brain endothelial cell line were used to explore activity of mature IL-1 alpha and IL-1 alpha at pH 7.4 and pH 6.2, an acidic pH that can be reached under inflammatory or ischemic conditions, alongside cathepsin D-cleaved 20-kDa IL-1 beta produced under acidic conditions. We report that mature IL-1 signaling at IL-1 receptor type 1 (IL-1R1) is maintained at pH 6.2, but the activity of the decoy receptor, IL-1R2, is reduced. Additionally, cathepsin D-cleaved 20-kDa IL-1 beta was minimally active at IL-1R1 and was not further cleaved to highly active 17-kDa IL-1 beta. Therefore formation of the 20-kDa form of IL-1 beta may prevent the generation of mature bioactive IL-1 beta and thus may limit inflammation.