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

Abstract

Tumor necrosis factor-α (TNFα) and transforming growth factor-β₁ (TGFβ₁) are potent peptide growth factors that are likely to play important roles in the development of interstitial pulmonary fibrosis (IPF). Previously we showed that TNFα and TGFβ₁ 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 TNFα receptor knockout mice are resistant to asbestos-induced fibrosis. Importantly, vectors that over-express TNFα cause inflammation and fibrogenesis along with increased TGFβ₁ production in C57Bl/6 mice. Recently we reported that TNFα activates the extracellular regulated kinase pathway in fibroblasts leading to a 200–400% increase in TGFβ₁ mRNA and protein. The mechanism of TNFα induction of TGFβ₁ expression appears to be complex, involving both transcriptional and post-transcriptional mechanisms. In asbestos-exposed animals, this TGFβ₁ is produced on alveolar surfaces in a latent form (controlled by binding of a latent associated peptide [LAP]) that must be activated for the TGFβ₁ 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 TGFβ₁ by oxidation of the LAP. Now, in preliminary findings, we have shown that over-expression of latent TGFβ₁ prior to asbestos exposure of fibrogenic-resistant TNFα 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 TGFβ₁, 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 TGFβ₁ 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 TNFα controls fibrogenesis by regulating TGFβ₁ expression and that one mechanism through which ROS induce lung fibrosis is by activating latent TGFβ ₁.

Keywords :

• Asbestos
• transforming growth factor-β1
• tumor necrosis factor-α
• reactive oxygen species
• lung fibrosis