| Interleukin-33 is biologically active independently of caspase-1 cleavage. | |
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MedLine Citation:
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PMID: 19465481 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Dominique Talabot-Ayer; Céline Lamacchia; Cem Gabay; Gaby Palmer |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-05-22 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 284 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-07-13 Completed Date: 2009-09-25 Revised Date: 2010-09-24 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 19420-6 Citation Subset: IM |
Affiliation:
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Division of Rheumatology, University Hospital, and Department of Pathology and Immunology, University of Geneva School of Medicine, 1211 Geneva 4, Switzerland. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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 |
| Chemical | |
Reg. No./Substance:
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0/IL33 protein, human; 0/Interleukin-1beta; 0/Interleukins; 0/Lipopolysaccharides; 0/Peptide Fragments; 0/Protein Precursors; 0/interleukin-33, mouse; 147336-22-9/Green Fluorescent Proteins; 16561-29-8/Tetradecanoylphorbol Acetate; EC 3.4.22.36/Caspase 1 |
| Comments/Corrections | |
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