Progressive pulmonary fibrosis is mediated by TGF-β isoform 1 but not TGF-β3

Abstract

Tissue repair is a well orchestrated biological process involving numerous soluble mediators, and an imbalance between these factors may result in impaired repair and fibrosis. Transforming growth factor (TGF) β is a key profibrotic element in this process and it is thought that its three isoforms act in a similar way. Here, we report that TGF-β3 administered to rat lungs using transient overexpression initiates profibrotic effects similar to those elicited by TGF-β1, but causes less severe and progressive changes. The data suggest that TGF-β3 does not lead to inhibition of matrix degradation in the same way as TGF-β1, resulting in non-fibrotic tissue repair. Further, TGF-β3 is able to downregulate TGF-β1 induced gene expression, suggesting a regulatory role of TGF-β3. TGF-β3 overexpression results in an upregulation of Smad proteins similar to TGF-β1, but is less efficient in inducing the ALK 5 and TGF-β type II receptor (TβRII). We provide evidence that this difference may contribute to the progressive nature of TGF-β1 induced fibrotic response, in contrast to the limited fibrosis observed following TGF-β3 overexpression. TGF-β3 is important in "normal wound healing", but is outbalanced by TGF-β1 in "fibrotic wound healing" in the lung.

Targeting TGF-β Signaling for Therapeutic Gain

“…The sparsity of reports of TGF-b3 involvement in cancer may be because of ascertainment bias (i.e., few studies have systematically examined the expression of all three ligands during tumorigenesis); alternatively, there is disincentive to report negative data (i.e., TGF-b3 may not be expressed). However, the question of which tissue and what cell types secrete the various ligands is critical when using ligand-specific drugs (Bedinger et al 2016), especially in the light of older reports that TGF-b1 and TGFb3 may have antagonistic effects (Li et al 1999;Ask et al 2008;Laverty et al 2009). In breast cancer, which has been most extensively studied in this respect, reports suggest that both TGF-b1 and TGF-b2 are functionally associated with a more invasive and early onset breast cancer, whereas TGF-b3 expression appears higher in more differentiated lobular breast tumors (Flanders and Wakefield 2009).…”

IPW-5371 Proves Effective as a Radiation Countermeasure by Mitigating Radiation-Induced Late Effects

“…The mRNA and/or protein levels of TGF-β are elevated in almost all fibrotic diseases and experimental models of fibrosis, including radiation-induced lung fibrosis (8)(9)(10)(11). TGF-β is a secreted protein that exists in three isoforms, TGF-β1, TGF-β2 and TGF-β3, although studies have linked the formation of lung fibrosis primarily to TGF-β1 and signaling through the canonical pathway involving Smad2/ Smad3 activation (12). Use of TGF-β receptor 1 (TGF-βRI) antagonists in the attenuation of pulmonary fibrosis has been well established in both radiation-and bleomycin-induced fibrosis (13)(14)(15).…”

TGF-β1 antisense therapy modulates expression of matrix metalloproteinases in keloid-derived fibroblasts

“…The major pathogenetic feature of fibrosis is represented by excessive accumulation of collagen and extracellular matrix (ECM) leading to progressive organ dysfunction in the liver, lung, kidney or skin. Ask et al described this phenomenon as a disturbed balance between degradation and accumulation of ECM in favor of accumulation (24). In normal wound healing, matrix metalloproteinases (MMPs), a family of secreted and membraneanchored proteinases, are essential to the ECM maturation phase by removing devitalized tissue and by re-epithelializating cutaneous wounds (25,26).…”