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

Talabot Frischknecht-Ayer, Dominique; Lamacchia, Céline; Gabay, Cem; Palmer-Lourenco, Gaby

doi:10.1074/jbc.M901744200

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Title		Interleukin-33 is biologically active independently of caspase-1 cleavage
Authors		Talabot Frischknecht-Ayer, Dominique Lamacchia, Céline Gabay, Cem Palmer-Lourenco, Gaby
Published in		The Journal of biological chemistry. 2009, vol. 284, no. 29, p. 19420-6
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
Identifiers		DOI: 10.1074/jbc.M901744200 PMID: 19465481
Full text		Article (Accepted version) (673 Kb) - Free access Other version: http://www.jbc.org/content/284/29/19420.long
Structures		Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie
Research groups		Biologie des cytokines de la famille de l'interleukine-1 (1022) Mécanisme de l'inflammation articulaire (44)
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. 19420-6. doi: 10.1074/jbc.M901744200 https://archive-ouverte.unige.ch/unige:5352