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-1α and IL-1β 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-1β 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-1β was minimally active at IL-1R1 and was not further cleaved to highly active 17-kDa IL-1β. Therefore formation of the 20-kDa form of IL-1β may prevent the generation of mature bioactive IL-1β and thus may limit inflammation.
From the Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
Michelle E
ME
Edye
From the Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom david.brough@manchester.ac.uk.
David
http://orcid.org/0000-0002-2250-2381
D
Brough
From the Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
Stuart M
http://orcid.org/0000-0001-9646-4456
SM
Allan
D000143:Acids / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D002402:Cathepsin D / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007375:Interleukin-1 / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D059748:Proteolysis; D015398:Signal Transduction
D000143:Acids; D007375:Interleukin-1; D011498:Protein Precursors; C043830:interleukin 1 precursor; D020170:Caspase 1; D002402:Cathepsin D
acidosis; caspase 1 (CASP1); cathepsin D; inflammation; innate immunity; interleukin 1 (IL-1); interleukin 1 receptor type II (IL-1R2)