TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis

Our plain-English summary of TNF-alpha inhibits asbestos-induced cytotoxicity via a NF-kappaB-dependent pathway, a possible mechanism for asbestos-induced oncogenesis, by H. Yang, M. Bocchetta, B. Kroczynska, et al (Proceedings of the National Academy of Sciences of the United States of America, 2006).

The study

• Authors: H. Yang, M. Bocchetta, B. Kroczynska, A.G. Elmishad, Y. Chen, Z. Liu, C. Bubici, B.T. Mossman, H.I. Pass, J.R. Testa, G. Franzoso, M. Carbone
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Published: 2006;103(27):10397-10402
• Cited by: 229 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Asbestos is the main cause of human malignant mesothelioma (MM). In vivo, macrophages phagocytize asbestos and, in response, release TNF-alpha and other cytokines that contribute to carcinogenesis through unknown mechanisms. In vitro, asbestos does not induce transformation of primary human mesothelial cells (HM); instead, asbestos is very cytotoxic to HM, causing extensive cell death. This finding raised an apparent paradox: How can asbestos cause MM if HM exposed to asbestos die? We found that asbestos induced the secretion of TNF-alpha and the expression of TNF-alpha receptor I in HM. Treatment of HM with TNF-alpha significantly reduced asbestos cytotoxicity. Through numerous technical approaches, including chemical inhibitors and small interfering RNA strategies, we demonstrate that, in HM, TNF-alpha activates NF-kappaB and that NF-kappaB activation leads to HM survival and resistance to the cytotoxic effects of asbestos. Our data show a critical role for TNF-alpha and NF-kappaB signaling in mediating HM responses to asbestos. TNF-alpha signaling through NF-kappaB-dependent mechanisms increases the percent of HM that survives asbestos exposure, thus increasing the pool of asbestos-damaged HM that are susceptible to malignant transformation. Cytogenetics supported this hypothesis, showing only rare, aberrant metaphases in HM exposed to asbestos and an increased mitotic rate with fewer irregular metaphases in HM exposed to both TNF-alpha and asbestos. Our findings provide a mechanistic rationale for the paradoxical inability of asbestos to transform HM in vitro, elucidate and underscore the role of TNF-alpha in asbestos pathogenesis in humans, and identify potential molecular targets for anti-MM prevention and therapy.

In plain English

This laboratory study used human mesothelial cells grown in culture, not people. The cells came from three donors, patients with fluid around the lungs from non-cancerous diseases. The authors exposed the cells to crocidolite asbestos and found that it killed them in a dose-dependent way: after 24 hours, 66% of cells survived a dose of 0.5 micrograms per square centimetre of dish, and 40% survived 5.0 micrograms per square centimetre. Crocidolite made the cells release TNF-alpha, an inflammatory signalling protein, and produce its receptor, TNF-R1. When cells were treated with TNF-alpha before asbestos, significantly fewer were killed. This protection disappeared when TNF-alpha was blocked with an antiserum. It also disappeared when the cell-survival pathway NF-kappaB was blocked, either chemically or genetically. In chromosome studies of cells from two donors, asbestos-treated cells rarely divided and showed abnormal chromosomes. Cells also given TNF-alpha had many dividing cells, and most of these had well-formed chromosomes without division irregularities. The authors concluded that, with TNF-alpha present, asbestos-damaged cells may divide rather than die, which may lead to mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell-culture experiments on primary human mesothelial cells, with each experiment done in triplicate
• Who was studied: Primary human mesothelial cells from patients who had accumulated pleural fluid because of nonmalignant diseases. Cells from three donors were used in all experiments, and cells from two donors in the chromosome (cytogenetic) analyses.
• Exposure: Crocidolite asbestos fibers from the Union Internationale Contre le Cancer, at doses from 0.2 to 10.0 micrograms per square centimetre of culture surface, with or without pretreatment with TNF-alpha at 10 ng per ml
• Main results:
  • Crocidolite killed mesothelial cells in a dose-dependent way. After 24 hours, 66% of cells were viable at 0.5 micrograms per square centimetre and 40% at 5.0 micrograms per square centimetre.
  • In mesothelial cells exposed to asbestos at 5.0 micrograms per square centimetre for 6, 12 or 24 hours, TNF-alpha mRNA was induced 3.5-, 4.8- or 7.2-fold, respectively.
  • Mesothelial cells exposed to crocidolite released TNF-alpha into the culture medium.
  • The TNF-alpha receptor TNF-R1 was induced in mesothelial cells after asbestos exposure, in a dose-dependent manner.
  • Pretreating mesothelial cells with TNF-alpha significantly reduced asbestos cytotoxicity.
  • Adding anti-TNF-alpha antiserum abolished the protective effect of TNF-alpha.
  • TNF-alpha caused the p65 subunit of NF-kappaB to move into the cell nucleus in mesothelial cells.
  • Blocking NF-kappaB with the chemical inhibitor Bay11-7082 suppressed the protective effect of TNF-alpha.
  • In cells where p65 (RelA) was reduced by RNA interference, the protective effect of TNF-alpha was abolished.
  • In chromosome analyses, cells treated with crocidolite alone showed rare metaphases (dividing cells), and nearly all had very poor chromosome morphology and premature separation of chromatids.
  • Cells pretreated with TNF-alpha before asbestos had numerous metaphases. Most were without mitotic irregularities and had good chromosome morphology.
• The authors' conclusion: The authors concluded that, in the presence of TNF-alpha, mesothelial cells that have accumulated genetic damage from asbestos may be more prone to divide rather than die, and that this may lead to malignant mesothelioma. They presented this as a possible mechanism.

Topics

Medical terms in this study, explained in our Lexicon: Oncogenesis, Malignant Mesothelioma, Macrophage, Cytokine, Carcinogenesis, Mesothelial Cells, Asbestos Exposure, Malignant Transformation.

Related studies

• Activated TNF-alpha/NF-kappaB signaling via down-regulation of Fas-associated factor 1 in asbestos-induced mesotheliomas from Arf knockout mice — D.A. Altomare, C.W. Menges, et al. (2009)
• Bortezomib inhibits nuclear factor-kappaB dependent survival and has potent in vivo activity in mesothelioma — A. Sartore-Bianchi, F. Gasparri, et al. (2007)
• Role of transcription factor NF-kappaB in asbestos-induced TNFalpha response from macrophages — N. Cheng, X. Shi, et al. (1999)
• Continuous exposure to chrysotile asbestos can cause transformation of human mesothelial cells via HMGB1 and TNF-α signaling — F. Qi, G. Okimoto, et al. (2013)
• Asbestos-induced mesothelioma: is fiber biopersistence really a critical factor? — E. Kagan (2013)
• Repression of GADD153/CHOP by NF-kappaB: a possible cellular defense against endoplasmic reticulum stress-induced cell death — S. Nozaki, G.W. Sledge, et al. (2001)

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