IL-33 isoforms and their associated bioactivity. IL-33 is synthesized as a 30 kD protein (full-length-IL-33, f-IL-33); however, alternative splicing can generate a 25 kD peptide (splice-IL-33, spIL-33), which possesses similar bioactivity to f-IL-33, but lacks caspase cleavage sites. During cellular apoptosis, f-IL-33 serves as a potential substrate for pro-apoptotic caspases (caspase-3 and caspase-7), generating smaller peptides of 20–22 kD with a marked reduction in bioactivity. Conversely, when secreted extracellularly, the proinflammatory activity of f-IL-33 may be potentiated in the context of a permissive, proinflammatory environment. In fact, Cathepsin G and elastase, released extracellularly by degranulating neutrophils, are able to cleave f-IL-33 into smaller isoforms (mature-IL-33, m-IL-33, 18–22 kD), which have been reported to display the greatest bioactivity.
