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.
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).
Sullivan
Deborah E
DE
Department of Microbiology and Immunology and the Lung Biology Program, Tulane University Health Sciences Center, New Orleans, Louisiana 70112, USA. dsulliva@tulane.edu
Ferris
Marybeth
M
Pociask
Derek
D
Brody
Arnold R
AR
D000818:Animals; D001194:Asbestos / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000276:immunology / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051785:Smad Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology
D002273:Carcinogens; D053779:Latent TGF-beta Binding Proteins; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D001194:Asbestos; D048049:Extracellular Signal-Regulated MAP Kinases