The latent form of TGFβ1 is induced by TNFα through an ERK specific pathway and is activated by asbestos-derived reactive oxygen species in vitro and in vivo

Tumor necrosis factor-alpha (TNF alpha) and transforming growth factor-beta 1 (TGF beta(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 TNF alpha and TGF beta(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 TNF alpha receptor knockout mice are resistant to asbestos-induced fibrosis. Importantly, vectors that over-express TNF alpha cause inflammation and fibrogenesis along with increased TGF beta(1) production in C57Bl/6 mice. Recently we reported that TNF alpha activates the extracellular regulated kinase pathway in fibroblasts leading to a 200-400% increase in TGF beta(1) mRNA and protein. The mechanism of TNF alpha induction of TGF beta(1) expression appears to be complex, involving both transcriptional and post-transcriptional mechanisms. In asbestos-exposed animals, this TGF beta(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 TGF beta(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 TGF beta(1) by oxidation of the LAP. Now, in preliminary findings, we have shown that over-expression of latent TGF beta(1) prior to asbestos exposure of fibrogenic-resistant TNF alpha 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 TGF beta(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 TGF beta 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 TNF alpha controls fibrogenesis by regulating TGF beta(1) expression and that one mechanism through which ROS induce lung fibrosis is by activating latent TGF beta(1).