The IL-1-Like Cytokine IL-33 Is Constitutively Expressed in the Nucleus of Endothelial Cells and Epithelial Cells In Vivo: A Novel ‘Alarmin’?
Open accessAbstract
BACKGROUND: Interleukin-33 (IL-33) is an IL-1-like cytokine ligand for the IL-1 receptor-related protein ST2, that activates mast cells and Th2 lymphocytes, and induces production of Th2-associated cytokines in vivo. We initially discovered IL-33 as a nuclear factor (NF-HEV) abundantly expressed in high endothelial venules from lymphoid organs, that associates with chromatin and exhibits transcriptional regulatory properties. This suggested that, similarly to IL-1alpha and chromatin-associated cytokine HMGB1, IL-33 may act as both a cytokine and a nuclear factor. Although the activity of recombinant IL-33 has been well characterized, little is known yet about the expression pattern of endogenous IL-33 in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that IL-33 is constitutively and abundantly expressed in normal human tissues. Using a combination of human tissue microarrays and IL-33 monoclonal and polyclonal antibodies, we found that IL-33 is a novel nuclear marker of the endothelium widely expressed along the vascular tree. We observed abundant nuclear expression of IL-33 in endothelial cells from both large and small blood vessels in most normal human tissues, as well as in human tumors. In addition to endothelium, we also found constitutive nuclear expression of IL-33 in fibroblastic reticular cells of lymphoid tissues, and epithelial cells of tissues exposed to the environment, including skin keratinocytes and epithelial cells of the stomach, tonsillar crypts and salivary glands. CONCLUSIONS/SIGNIFICANCE: Together, our results indicate that, unlike inducible cytokines, IL-33 is constitutively expressed in normal human tissues. In addition, they reveal that endothelial cells and epithelial cells constitute major sources of IL-33 in vivo. Based on these findings, we speculate that IL-33 may function, similarly to the prototype 'alarmin' HMGB1, as an endogenous 'danger' signal to alert the immune system after endothelial or epithelial cell damage during trauma or infection.
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IL-33 is constitutively expressed at high levels and stored in the nucleus of endothelial and epithelial cells.
“IL-33 is constitutive expressed at high levels and stored in the nucleus of endothelial and epithelial cells [28].”
Intracellular stores of biologically active pro-inflammatory cytokines and chemokines, such as IL-1α and IL-33, may be released by necrotic cells.
“Similarly, in addition to intracellular molecules, intracellular stores of biologically active pro-inflammatory cytokines and chemokines, such as IL-1α15 and IL-33 (REF. 16), may be released by necrotic cells.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [16]
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- Authors
- Moussion, C., Ortega, N., & Girard, J.-P.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Girard, Jean-Philippe
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2008-10-06
- Volume
- 3
- Issue
- 10
- Pages
- e3331
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2556082
- OpenAlex
- W1968955229
- Cited by
- 1,179
- References
- 43
- Citations by year
- 2026: 33 · 2025: 38 · 2024: 45 · 2023: 59 · 2022: 78 · 2021: 82 · 2020: 79 · 2019: 73 · 2018: 85 · 2017: 83 · 2016: 86 · 2015: 83 · 2014: 78 · 2013: 73 · 2012: 78
- FWCI
- 17.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Agence Nationale de la Recherche
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- IL-33, nuclear expression, endothelial cells, epithelial cells, alarmins, damage-associated molecular patterns, ST2, high endothelial venules, fibroblastic reticular cells, keratinocytes, HMGB1, tissue distribution
- MeSH terms
- Interleukin-33, Actins, Cell Nucleus, Desmin, Epithelial Cells, Fluorescent Dyes, Humans, Immunohistochemistry, Indoles, Interleukin-1, Interleukins, Cytokines, Inflammation Mediators, Endothelial Cells
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