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

Area of Science:

• Biochemistry
• Immunology
• Cell Biology

Background:

• Noncommunicable diseases (NCDs) are a major global health burden, significantly exacerbated by inflammation.
• Interleukin-1 (IL-1) is a key mediator of inflammation and implicated in various NCDs.
• Acidosis is a characteristic feature of the inflammatory microenvironment, necessitating investigation of IL-1 signaling under these conditions.

Purpose of the Study:

• To investigate the activity of mature IL-1α and IL-1β signaling at physiological (pH 7.4) and acidic (pH 6.2) conditions.
• To explore the impact of acidic pH on the activity of the decoy receptor IL-1R2.
• To assess the activity of cathepsin D-cleaved 20-kDa IL-1β produced under acidic conditions.

Main Methods:

• Utilized a HEK-IL-1 reporter assay to measure IL-1 activity.
• Employed a brain endothelial cell line to model inflammatory conditions.
• Compared IL-1 signaling and receptor activity at pH 7.4 and pH 6.2.

Main Results:

• Mature IL-1 signaling via IL-1 receptor type 1 (IL-1R1) was sustained at acidic pH 6.2.
• The activity of the decoy receptor IL-1R2 was significantly reduced at pH 6.2.
• Cathepsin D-cleaved 20-kDa IL-1β exhibited minimal activity at IL-1R1 and was not further processed to the highly active 17-kDa form.

Conclusions:

• Acidic conditions characteristic of inflammation do not abolish IL-1 signaling at the functional receptor IL-1R1.
• Reduced IL-1R2 activity under acidic conditions may enhance IL-1 signaling.
• The formation of 20-kDa IL-1β under acidic conditions may serve as a regulatory mechanism to limit the generation of mature, bioactive IL-1β, thereby potentially mitigating inflammation.