The latent form of TGFbeta(1) is induced by TNFalpha through an ERK specific pathway and is activated by asbestos-derived reactive oxygen species in vitro and in vivo

Our plain-English summary of The latent form of TGFbeta(1) is induced by TNFalpha through an ERK specific pathway and is activated by asbestos-derived reactive oxygen species in vitro and in vivo, by D.E. Sullivan, M. Ferris, D. Pociask, et al (Journal of Immunotoxicology, 2008).

The study

• Authors: D.E. Sullivan, M. Ferris, D. Pociask, A.R. Brody
• Journal: Journal of Immunotoxicology
• Published: 2008;5(2):145-9
• Cited by: 54 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Tumor necrosis factor-alpha (TNFalpha) and transforming growth factor-beta(1) (TGFbeta(1)) are potent peptide growth factors that are likely to play important roles in the development of interstitial pulmonary fibrosis (IPF). Previously we showed that TNFalpha and TGFbeta(1) are up-regulated in macrophages, epithelial and mesenchymal cells early after exposure to chrysotile asbestos, particularly at sites of fiber deposition in vivo. We also showed that TNFalpha receptor knockout mice are resistant to asbestos-induced fibrosis. Importantly, vectors that over-express TNFalpha cause inflammation and fibrogenesis along with increased TGFbeta(1) production in C57Bl/6 mice. Recently we reported that TNFalpha activates the extracellular regulated kinase pathway in fibroblasts leading to a 200-400% increase in TGFbeta(1) mRNA and protein. The mechanism of TNFalpha induction of TGFbeta(1) expression appears to be complex, involving both transcriptional and post-transcriptional mechanisms. In asbestos-exposed animals, this TGFbeta(1) is produced on alveolar surfaces in a latent form (controlled by binding of a latent associated peptide [LAP]) that must be activated for the TGFbeta(1) to bind to its receptors and induce its multiple biological effects. Thus, we recently reported that, in vitro, reactive oxygen species (ROS) derived from chrysotile and crocidolite asbestos activate TGFbeta(1) by oxidation of the LAP. Now, in preliminary findings, we have shown that over-expression of latent TGFbeta(1) prior to asbestos exposure of fibrogenic-resistant TNFalpha receptor knockout mice produces asbestos lesions with the same severity as seen in normal C57/Bl6 mice. This finding plus the demonstration of increased amounts of TGFbeta(1), increased Smad activation and amelioration of the developing disease by treating the mice with an anti-oxidant all support the concept that, in vivo, latent TGFbeta(1) is activated by asbestos-generated oxygen radicals and consequently mediates at least a component of the consequent fibrogenesis. Taken together, these findings support the postulate that TNFalpha controls fibrogenesis by regulating TGFbeta(1) expression and that one mechanism through which ROS induce lung fibrosis is by activating latent TGFbeta(1).

In plain English

This short article reviewed the authors' own laboratory work on how two growth factors, TNFα and TGFβ1, may drive lung scarring (fibrosis) after asbestos exposure, and it added new and preliminary results. No people were studied. In an earlier study, the authors reported that mouse lung fibroblasts treated with TNFα raised their TGFβ1 messenger RNA to 200 to 400% of untreated cells by 12 hours. Drugs that block a signaling route called ERK significantly blocked this increase. In this article, other mouse and human lung cell lines also responded to TNFα, and mice given a virus producing TNFα showed more activated ERK and more TGFβ1 in their lungs. TGFβ1 is made in an inactive (latent) form. Mice lacking TNFα receptors were given extra latent TGFβ1 and then exposed to chrysotile asbestos. They had more active TGFβ1 and more severe asbestos lesions than the control groups. The antioxidant Tempol reduced both. The authors concluded that TNFα's fibrotic effects may work partly through raising TGFβ1.

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: Brief review of the authors' own laboratory research, with some new, unpublished and preliminary results from cell culture experiments and mouse experiments
• Who was studied: Mice genetically engineered to lack TNFα receptors (resistant to asbestos fibrosis), plus mouse and human lung cells in culture; numbers of animals not given
• Exposure: Chrysotile asbestos given to mice 7 days after a virus that over-expresses latent TGFβ1 (or an empty control virus); TNFα applied to lung cells in culture. The authors' earlier in vitro work used chrysotile and crocidolite.
• Main results:
  • In the authors' earlier study, TNFα raised TGFβ1 mRNA in fibroblasts from adult C57 mouse lungs within 2 hours, peaking at 200 to 400% of untreated controls after 12 hours and lasting 24 hours
  • Mouse alveolar epithelial cells (C10), human alveolar epithelial cells (A549) and human lung fibroblasts (HFL1) also increased TGFβ1 expression in response to TNFα
  • In the earlier study, drugs that block ERK1/ERK2 significantly blocked the TNFα-induced rise in TGFβ1 in mouse lung fibroblasts, while inhibitors of JNK or p38 had little effect
  • Mice given a virus over-expressing TNFα had significant increases in activated (phosphorylated) ERK1/ERK2 and TGFβ1 protein in the lungs compared with mice given a control virus
  • In Swiss 3T3 fibroblasts, blocking transcription with actinomycin D partially blocked the TNFα-induced rise in TGFβ1 mRNA
  • In the earlier study, TGFβ1 mRNA had a half-life of about 15 hours in untreated cells, while no breakdown was detected after 24 hours in TNFα-treated cells
  • TNFα receptor knockout mice given latent TGFβ1 and then asbestos had significantly more active TGFβ1 in whole lung, more Smad-2 activation, and more severe asbestos lesions than mice given the empty virus plus asbestos, or the TGFβ1 virus alone
  • Latent TGFβ1 over-expressing mice treated with the antioxidant Tempol before asbestos exposure had less active TGFβ1, less Smad-2 activation and less severe lesions than untreated mice given the same virus and asbestos
• The authors' conclusion: The authors concluded that the fibrosis-promoting effects of TNFα may work at least partly by raising TGFβ1 through the ERK pathway, and that asbestos-derived reactive oxygen species provide a way to activate latent TGFβ1
• Limitations the authors state:
  • The authors stated it remains to be determined whether reactive oxygen species activate latent TGFβ1 in living animals directly, or indirectly through enzymes (proteases)
  • The authors described the latent TGFβ1 mouse findings as preliminary

Topics

Medical terms in this study, explained in our Lexicon: Reactive Oxygen Species (ROS), Tumor Necrosis Factor-alpha (TNF-α), Transforming Growth Factor-beta (TGF-β), Interstitial, Pulmonary Fibrosis, Macrophage, Chrysotile, Deposition.

Related studies

• Iron and reactive oxygen species in the asbestos-induced tumor necrosis factor-alpha response from alveolar macrophages — P.P. Simeonova, M.I. Luster (1995)
• Mitochondria-derived reactive intermediate species mediate asbestos-induced genotoxicity and oxidative stress-responsive signaling pathways — S.X. Huang, M.A. Partridge, et al. (2012)
• Asbestos-derived reactive oxygen species activate TGF-beta1 — D.A. Pociask, P.J. Sime, et al. (2004)
• Wollastonite fibers in vitro generate reactive oxygen species able to lyse erythrocytes and activate the complement alternate pathway — M. Governa, L. Camilucci, et al. (1998)
• Beyond foreign-body-induced carcinogenesis: impact of reactive oxygen species derived from inflammatory cells in tumorigenic conversion and tumor progression — F. Okada (2007)
• Mitochondria-derived reactive oxygen species drive GANT61-induced mesothelioma cell apoptosis — C.B. Lim, C.M. Prêle, et al. (2015)

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