en
Scientific article
Open access
English

Interleukin-33 is biologically active independently of caspase-1 cleavage

Published inThe Journal of biological chemistry, vol. 284, no. 29, p. 19420-19426
Publication date2009
Abstract

The new interleukin (IL)-1 family cytokine IL-33 is synthesized as a 30-kDa precursor. Like pro-IL-1beta, human pro-IL-33 was reported to be cleaved by caspase-1 to generate an 18-kDa fragment, which is sufficient to activate signaling by the IL-33 receptor T1/ST2. However, the proposed caspase-1 cleavage site is poorly conserved between species. In addition, it is not clear whether caspase-1 cleavage of pro-IL-33 occurs in vivo and whether, as for IL-1beta, this cleavage is a prerequisite for IL-33 secretion and bioactivity. In this study, we further investigated caspase-1 cleavage of mouse and human pro-IL-33 and assessed the potential bioactivity of the IL-33 precursor. We observed the generation of a 20-kDa IL-33 fragment in cell lysates, which was enhanced by incubation with caspase-1. However, in vitro assays of mouse and human pro-IL-33 indicated that IL-33 is not a direct substrate for this enzyme. Consistently, caspase-1 activation in THP-1 cells induced cleavage of pro-IL-1beta but not of pro-IL-33, and activated THP-1 cells released full-length pro-IL-33 into culture supernatants. Finally, addition of full-length pro-IL-33 induced T1/ST2-dependent IL-6 secretion in mast cells. However, we observed in situ processing of pro-IL-33 in mast cell cultures, and it remains to be determined whether full-length pro-IL-33 itself indeed represents the bioactive species. In conclusion, our data indicate that pro-IL-33 is not a direct substrate for caspase-1. In addition, our results clearly show that caspase-1 cleavage is not required for pro-IL-33 secretion and bioactivity, highlighting major differences between IL-1beta and IL-33.

Keywords
  • Animals
  • Blotting, Western
  • Caspase 1/metabolism
  • Cell Line
  • Cells, Cultured
  • Enzyme Activation/drug effects
  • Green Fluorescent Proteins/genetics/metabolism
  • Humans
  • Interleukin-1beta/metabolism
  • Interleukins/chemistry/genetics/metabolism
  • Lipopolysaccharides/pharmacology
  • Mice
  • Microscopy, Confocal
  • Monocytes/cytology/drug effects/metabolism
  • Peptide Fragments/metabolism
  • Protein Precursors/genetics/metabolism
  • Tetradecanoylphorbol Acetate/pharmacology
  • Transfection
Citation (ISO format)
TALABOT FRISCHKNECHT-AYER, Dominique et al. Interleukin-33 is biologically active independently of caspase-1 cleavage. In: The Journal of biological chemistry, 2009, vol. 284, n° 29, p. 19420–19426. doi: 10.1074/jbc.M901744200
Main files (1)
Article (Accepted version)
accessLevelPublic
Identifiers
ISSN of the journal0021-9258
548views
421downloads

Technical informations

Creation03/05/2010 1:34:00 PM
First validation03/05/2010 1:34:00 PM
Update time03/14/2023 3:24:43 PM
Status update03/14/2023 3:24:43 PM
Last indexation05/02/2024 11:29:29 AM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack