Interleukin-1β–Driven Inflammation Promotes the Development and Invasiveness of Chemical Carcinogen–Induced Tumors
Abstract
The role of microenvironment interleukin 1 (IL-1) on 3-methylcholanthrene (3-MCA)–induced carcinogenesis was assessed in IL-1–deficient mice, i.e., IL-1β−/−, IL-1α−/−, IL-1α/β−/− (double knockout), and mice deficient in the naturally occurring inhibitor of IL-1, the IL-1 receptor antagonist (IL-1Ra). Tumors developed in all wild-type (WT) mice, whereas in IL-1β–deficient mice, tumors developed slower and only in some of the mice. In IL-1Ra–deficient mice, tumor development was the most rapid. Tumor incidence was similar in WT and IL-1α–deficient mice. Histologic analyses revealed fibrotic structures forming a capsule surrounding droplets of the carcinogen in olive oil, resembling foreign body–like granulomas, which appeared 10 days after injection of 3-MCA and persisted until the development of local tumors. A sparse leukocyte infiltrate was found at the site of carcinogen injection in IL-1β–deficient mice, whereas in IL-1Ra–deficient mice, a dense neutrophilic infiltrate was observed. Treatment of IL-1Ra–deficient mice with recombinant IL-1Ra but not with an inhibitor of tumor necrosis factor abrogated the early leukocytic infiltrate. The late leukocyte infiltrate (day 70), which was dominated by macrophages, was also apparent in WT and IL-1α–deficient mice, but was nearly absent in IL-1β–deficient mice. Fibrosarcoma cell lines, established from 3-MCA–induced tumors from IL-1Ra–deficient mice, were more aggressive and metastatic than lines from WT mice; cell lines from IL-1–deficient mice were the least invasive. These observations show the crucial role of microenvironment-derived IL-1β, rather than IL-1α, in chemical carcinogenesis and in determining the invasive potential of malignant cells. [Cancer Res 2007;67(3):1062–71]
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IL-1β has been proposed to contribute to asbestos-induced mesothelioma by influencing human mesothelial cell growth, and inflammation driven by IL-1β is known to promote tumour development and invasion in vivo.
“An important role for IL-1β has been proposed in the pathogenesis of asbestos-induced mesothelioma by regulating human mesothelial cell proliferation (23) and IL-1β-driven inflammation is well known to promote the development and invasiveness of several tumour types in vivo (24).”
From Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica (2008) · cites this paper as [24]
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- Authors
- Krelin, Y., Voronov, E., Dotan, S., Elkabets, M., Reich, E., Fogel, M., Huszar, M., Iwakura, Y., Segal, S., Dinarello, C. A., & Apte, R. N.
- Affiliations
- Ben-Gurion University of the Negev (IL)
- Kaplan Medical Center (IL)
- Institute of Medical Science, The University of Tokyo (JP)
- University of Colorado Denver (US)
- Venue
- Cancer Research
- Published
- 2007-02-01
- Volume
- 67
- Issue
- 3
- Pages
- 1062-1071
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2056666823
- Cited by
- 285
- References
- 50
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 11 · 2023: 13 · 2022: 21 · 2021: 10 · 2020: 16 · 2019: 15 · 2018: 17 · 2017: 13 · 2016: 13 · 2015: 15 · 2014: 16 · 2013: 21 · 2012: 22
- FWCI
- 5.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL68743, P01HL068743)
- National Cancer Institute (CA 046934, P30CA046934)
- National Institute of Allergy and Infectious Diseases (AI‑15614)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
- Keywords
- IL-1β, interleukin-1 alpha, interleukin-1 receptor antagonist, chemical carcinogenesis, 3-methylcholanthrene, tumor microenvironment, tumor invasion, metastasis, fibrosarcoma, foreign body granuloma, macrophages, neutrophils
- MeSH terms
- Animals, Carcinogens, Cocarcinogenesis, Female, Fibrosarcoma, Inflammation, Leukocytes, Methylcholanthrene, Mice, Inbred BALB C, Neoplasm Invasiveness, Mice, Knockout, Mice, Interleukin-1alpha, Interleukin-1beta, Interleukin 1 Receptor Antagonist Protein
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