The Serpin Proteinase Inhibitor 9 Is an Endogenous Inhibitor of Interleukin 1β–Converting Enzyme (Caspase-1) Activity in Human Vascular Smooth Muscle Cells
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Interleukin-1beta-converting enzyme (ICE, caspase-1) regulates key steps in inflammation and immunity, by activating the proinflammatory cytokines interleukin (IL-)1beta and IL-18, or mediating apoptotic processes. We recently provided evidence for the regulation of caspase-1 activity via an endogenous inhibitor expressed by human vascular smooth muscle cells (SMCs) (Schönbeck, U., M. Herzberg, A. Petersen, C. Wohlenberg, J. Gerdes, H.-D. Flad, and H. Loppnow. 1997. J. Exp. Med. 185:1287-1294). However, the molecular identity of this endogenous inhibitor remained undefined. We report here that the serine proteinase inhibitor (serpin) PI-9 accounts for the endogenous caspase-1 inhibitory activity in human SMCs and prevents processing of the enzyme's natural substrates, IL-1beta and IL-18 precursor. Treatment of SMC lysates with anti-PI-9 antibody abrogated the caspase-1 inhibitory activity and coprecipitated the enzyme, demonstrating protein-protein interaction. Furthermore, PI-9 antisense oligonucleotides coordinately reduced PI-9 expression and promoted IL-1beta release. Since SMCs comprise the majority of cells in the vascular wall, and because IL-1 is implicated in atherogenesis, we tested the biological validity of our in vitro findings within human atheroma in situ. The unaffected arterial wall contains abundant and homogeneously distributed PI-9. In human atherosclerotic lesions, however, PI-9 expression correlated inversely with immunoreactive IL-1beta, supporting a potential role of the endogenous caspase-1 inhibitor in this chronic inflammatory disease. Thus, our results provide new insights into the regulation of this enzyme involved in immune and inflammatory processes of chronic inflammatory diseases, and point to an endogenous antiinflammatory action of PI-9, dysregulated in a prevalent human disease.
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PI-9 acts by directly binding and inhibiting caspase-1.
“In addition, other inhibitors such as PI-9 act by directly binding and inhibiting caspase-1 (40,41).”
From Sustained Inflammasome Activity in Macrophages Impairs Wound Healing in Type 2 Diabetic Humans and Mice (2014) · cites this paper as [40]
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- Authors
- Young, J. L., Sukhova, G. K., Foster, D., Kisiel, W., Libby, P., & Schönbeck, U.
- Affiliations
- Brigham and Women's Hospital (US)
- bZymoGenetics, Incorporated, Seattle, Washington 93102
- University of New Mexico (US)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2000-05-01
- Volume
- 191
- Issue
- 9
- Pages
- 1535-1544
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2213432
- OpenAlex
- W2171074690
- Cited by
- 133
- References
- 58
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 6 · 2019: 6 · 2018: 1 · 2017: 5 · 2016: 2 · 2015: 3 · 2014: 1 · 2013: 10 · 2012: 7
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01hl034636-23)
- National Heart, Lung, and Blood Institute (R37HL034636, R01-HL034636, HL-34636)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- caspase-1, IL-1β, IL-18, vascular smooth muscle cells, protein-protein interaction, atherosclerosis, inflammation, anti-inflammatory regulation, atherosclerotic plaque
- MeSH terms
- Arteries, Arteriosclerosis, Gene Expression Regulation, Humans, Interleukin-1, Interleukins, Muscle, Smooth, Vascular, Protein Precursors, Protein Processing, Post-Translational, Serpins, Interleukin-18, Caspase Inhibitors
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