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IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo
Open accessAbstract
Recent studies indicate that IL-1α functions intracellularly in pathways independent of its cell surface receptors by translocating to the nucleus and regulating transcription. Similarly, the chromatin-associated protein HMGB1 acts as both a nuclear factor and a secreted proinflammatory cytokine. Here, we show that IL-33, an IL-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines, is an endothelium-derived, chromatin-associated nuclear factor with transcriptional repressor properties. We found that IL-33 is identical to NF-HEV, a nuclear factor preferentially expressed in high endothelial venules (HEV), that we previously characterized. Accordingly, in situ hybridization demonstrated that endothelial cells constitute a major source of IL-33 mRNA in chronically inflamed tissues from patients with rheumatoid arthritis and Crohn's disease. Immunostaining with three distinct antisera, directed against the N-terminal part and IL-1-like C-terminal domain, revealed that IL-33 is a heterochromatin-associated nuclear factor in HEV endothelial cells in vivo . Association of IL-33 with heterochromatin was also observed in human and mouse cells under living conditions. In addition, colocalization of IL-33 with mitotic chromatin was noted. Nuclear localization, heterochromatin-association, and targeting to mitotic chromosomes were all found to be mediated by an evolutionarily conserved homeodomain-like helix–turn–helix motif within the IL-33 N-terminal part. Finally, IL-33 was found to possess transcriptional repressor properties, associated with the homeodomain-like helix–turn–helix motif. Together, these data suggest that, similarly to IL1α and HMGB1, IL-33 is a dual function protein that may function as both a proinflammatory cytokine and an intracellular nuclear factor with transcriptional regulatory properties.
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“IL-33 is highly expressed within endothelial cells in the synovium of patients with rheumatoid arthritis87, and IL-33-deficient mice have reduced neutrophil migration in an experimental model of rheumatoid arthritis88, but the actual role of this cytokine in the pathogenesis of rheumatoid arthritis or other sterile inflammatory diseases remains to be determined.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [87]
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Metadata
- Authors
- Carriere, V., Roussel, L., Ortega, N., Lacorre, D.-A., Americh, L., Aguilar, L., Bouche, G., & Girard, J.-P.
- Affiliations
- *Laboratoire de Biologie Vasculaire, Equipe Labellisée “La Ligue 2006,” Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5089, 205 Route de Narbonne, 31077 Toulouse, France; and
- Centre National de la Recherche Scientifique (FR)
- Endocube, Prologue Biotech, BP700, Rue Pierre et Marie Curie, 31319 Labège Cedex, France
- Corresponding author
- Girard, Jean-Philippe
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-01-02
- Volume
- 104
- Issue
- 1
- Pages
- 282-287
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1765450
- OpenAlex
- W2093396768
- Cited by
- 966
- References
- 38
- Citations by year
- 2026: 20 · 2025: 29 · 2024: 30 · 2023: 49 · 2022: 50 · 2021: 51 · 2020: 47 · 2019: 51 · 2018: 58 · 2017: 55 · 2016: 64 · 2015: 70 · 2014: 52 · 2013: 56 · 2012: 72
- FWCI
- 12.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Association pour la Recherche sur le Cancer
- Drug Applied Research Center, Tabriz University of Medical Sciences
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- IL-33, ST2 receptor, heterochromatin, nuclear factors, transcriptional repressor, endothelial cells, high endothelial venules, rheumatoid arthritis, Crohn's disease, chronic inflammation, HMGB1
- MeSH terms
- Interleukin-33, Interleukin-1 Receptor-Like 1 Protein, Animals, Arthritis, Rheumatoid, Crohn Disease, HeLa Cells, Heterochromatin, Humans, Interleukins, Membrane Proteins, Mitosis, Nuclear Proteins, Receptors, Cell Surface, Repressor Proteins, RNA, Messenger, 3T3 Cells, Conserved Sequence, Receptors, Interleukin, Nuclear Localization Signals, Amino Acid Motifs, Endothelial Cells, Mice
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