Liver portal fibrosis in dioxin receptor-null mice that overexpress the latent transforming growth factor-beta-binding protein-1.

Mice lacking aryl hydrocarbon (dioxin) receptor (AhR) had variable degree of hepatic fibrosis and altered liver architecture. Transforming growth factor-beta (TGF-beta), a major profibrogenic molecule in the liver, is localized to the extracellular matrix by its association to the latent TGF-beta-binding protein-1 (LTBP-1). Very recently, LTBP-1 has been shown to be negatively regulated by the AhR. Embryonic fibroblasts from AhR-null (AhR(-/-)) mice overexpress LTBP-1 and secrete four times more active TGF-beta than wild-type fibroblasts. To test whether TGF-beta and LTBP-1 overexpression colocalize within the fibrotic nodule of AhR(-/-) liver, we have characterized this hepatic portal fibrosis using collagen protein staining, immunohistochemistry and in situ hybridization. LTBP-1 mRNA and protein were overexpressed in the fibrotic region and colocalized with other indicators of fibrosis such as collagen and fibronectin and the fibroblast marker proteins alpha-actin and vimentin. TGF-beta protein also colocalized with fibrosis, although in contrast, TGF-beta mRNA expression, rather than restricted to the fibrotic compartment, was present throughout the hepatic parenchyma and exhibited similar levels in wild-type and AhR(-/-) mice. These results suggest that LTBP-1 targets TGF-beta to specific areas of the liver and that the AhR could be a negative regulator of liver fibrosis, possibly through the control of LTBP-1 and TGF-beta activities.