Increased production of matrix metalloproteinase-7 (MMP-7) by asbestos exposure enhances tissue migration of human regulatory T-like cells

Our plain-English summary of Increased production of matrix metalloproteinase-7 (MMP-7) by asbestos exposure enhances tissue migration of human regulatory T-like cells, by S. Lee, S. Yamamoto, B. Srinivas, et al (Toxicology, 2021).

The study

• Authors: S. Lee, S. Yamamoto, B. Srinivas, Y. Shimizu, N. Sada, K. Yoshitome, T. Ito, N. Kumagai-Takei, Y. Nishimura, T. Otsuki
• Journal: Toxicology
• Published: 2021;452:152717
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The effects of asbestos on immunocompetent cells have been investigated. In particular, attention was paid to regulatory T cell function, which was observed using the HTLV-1 immortalized human polyclonal T cell line MT-2. Exposure to asbestos (approximately more than 25 μg/mL for 1-3 day) induced apoptosis, and we observed an increase in regulatory T cell function and acceleration of the cell cycle with continuous exposure to low concentrations of asbestos (5-10 μg/mL for more than eight months). Furthermore, cDNA microarray analysis in this study revealed that expression of matrix metalloproteinase-7 (MMP-7) was markedly higher in exposed sublines compared to original MT-2 cells. It was determined that MMP-7 had no effect on Treg function, as determined by examination of sublines and by addition of recombinant MMP-7 and neutralizing antibodies or inhibitors of MMP-7. However, when examining melting of the extracellular matrix (an MMP-7-mediated event) or the extent to which the MT-2 parent strain or long-term exposed subline cells pass through a fibronectin-coated filter, more filter passes were observed for the subline. These results suggest that the effect of asbestos fibers on Treg cells results in excessive migration of the tumor microenvironment through hypersecretion of MMP-7 together with an increase in suppressive function and enhancement of cell cycle progression. Therefore, one possible way to prevent the development of asbestos-induced cancer is to reduce the function (including MMP-7 production) or amount of Treg cells by physiologically active substances or food ingredients. Alternatively, it may be possible to invoke immune checkpoint treatments when carcinogenesis occurs.

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In plain English

This laboratory study used the HTLV-1 immortalised human polyclonal T cell line MT-2 (called Org), which has regulatory T (Treg)-like function. It also used sublines kept in culture for more than eight months with chrysotile B (CB1, 10 micrograms per mL) or crocidolite (CR1, 25 micrograms per mL). cDNA microarray showed matrix metalloproteinase-7 (MMP-7) as the greatest change in CB1 versus Org. Real-time RT-PCR confirmed significantly higher MMP-7 in CB1, while CR1 showed only a tendency (p = 0.072). MMP-7 was barely detectable in Org culture supernatants but abundant in CB1 and CR1 supernatants. In suppression assays with responder T cells from healthy volunteers, MMP-7 knock-down, recombinant MMP-7, an MMP-7 inhibitor and a neutralising antibody produced no significant differences in suppressive function. CB1 cells crossed a fibronectin-coated filter in significantly greater numbers than Org. The MMP-7 inhibitor reduced CB1 migration to 60.86 percent of the level in vehicle (DMSO)-treated cells (standard deviation 17.27, p = 0.0059), but did not significantly change Org migration. The authors concluded that asbestos-exposed Treg-like cells may migrate excessively through MMP-7 hypersecretion.

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: in vitro cell-line experiment: human T cell line MT-2 and sublines continuously exposed to asbestos, with gene expression, knock-down, Treg function and migration assays
• Who was studied: The MT-2 (Org) cell line, its asbestos-exposed sublines CB1 and CR1, MMP-7 knock-down clones and shRNA control clones, plus peripheral blood cells from healthy volunteers; Kawasaki Medical School, Kurashiki, Japan
• Exposure: Continuous culture with chrysotile B (10 micrograms per mL) or crocidolite (25 micrograms per mL) for more than eight months; iron content of CB 3.73% and CR 39.12%
• Main results:
  • In the cDNA microarray comparing CB1 with Org, MMP-7 showed the greatest change and was highly expressed in CB1
  • By real-time RT-PCR, MMP-7 was significantly higher in CB1 than Org; for CR1 the difference was not statistically significant (p = 0.072) because of large variability
  • MMP-7 protein was barely detected in Org culture supernatants but much larger amounts were found in CB1 and CR1 supernatants
  • In a representative suppression assay the non-dividing responder T cell fraction was 15% with Org, 42% with CB1, 36% with the MMP-7 knock-down clone KD3 and 47% with the shRNA control clone; CB1, sh-control and KD3 did not differ significantly
  • Recombinant MMP-7, the MMP-7 inhibitor and the neutralising antibody produced no significant differences in responder T cell proliferation or suppressive function in the MT-2(-), Org or CB1 groups
  • Vehicle-treated CB1 cells migrated through the fibronectin-coated filter significantly more than vehicle-treated Org cells. Relative to vehicle (DMSO)-treated cells, the MMP-7 inhibitor reduced CB1 migration to 60.86 percent (mean, standard deviation 17.27; p = 0.0059). Org migration fell to 92.9 percent of its DMSO control, with no significant change.
• The authors' conclusion: The authors concluded that highly secreted MMP-7 from long-term asbestos-exposed MT-2 sublines had no effect on Treg function. They concluded that the greater passage of subline cells through a fibronectin-coated filter indicates that asbestos fibers cause excessive migration of Treg cells into the tumor microenvironment through MMP-7 hypersecretion, alongside increased activity and cell cycle progression.
• Limitations the authors state:
  • The authors state the accuracy of their cell-line Treg model has not been evaluated
  • The authors could not examine Treg function from tissue surrounding tumors in malignant mesothelioma
  • The authors state the molecular mechanism producing the MMP-7 overexpression remains unclear
  • A high molecular weight band on Western blots of cell lysates could not be identified

Topics

Medical terms in this study, explained in our Lexicon: Asbestos Exposure, Apoptosis, Tumor Microenvironment, Carcinogenesis.

Related studies

• Aberrant expression of FoxP3 in a human T cell line possessing regulatory T cell‑like function and exposed continuously to asbestos fibers — M. Maeda, H. Matsuzaki, et al. (2018)
• Accelerated cell cycle progression of human regulatory T cell-like cell line caused by continuous exposure to asbestos fibers — S. Lee, H. Matsuzaki, et al. (2017)
• Enhancement of regulatory T cell-like suppressive function in MT-2 by long-term and low-dose exposure to asbestos — C. Ying, M. Maeda, et al. (2015)
• The Effects of Asbestos Fibers on Human T Cells — N. Kumagai-Takei, S. Lee, et al. (2020)
• Hepatocyte growth factor/scatter factor enhances the invasion of mesothelioma cell lines and the expression of matrix metalloproteinases — P. Harvey, I.M. Clark, et al. (2000)
• Chronic exposure to asbestos enhances TGF-β1 production in the human adult T cell leukemia virus-immortalized T cell line MT-2 — M. Maeda, Y. Chen, et al. (2014)

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