IL-13 Induces Connective Tissue Growth Factor in Rat Hepatic Stellate Cells via TGF-β–Independent Smad Signaling

Abstract

Connective tissue growth factor (CTGF) plays a central role in stimulating extracellular matrix deposition in the liver, and hence is considered a critical mediator of TGF-β–dependent fibrogenesis. Hepatic stellate cells (HSCs) are known as the major source of CTGF in damaged liver. However, previous studies revealed that IL-13, rather than TGF-β, represents the predominant inducer of CTGF expression in HSCs. We now dissected IL-13 downstream signaling that modulates CTGF expression in HSCs. IL-13 induces a time- and dosage-dependent increase of CTGF in a TGF-β–independent manner. This process requires participation of different Smad proteins and their upstream receptor kinases (activin receptor-like kinases). Smad1 and Smad2 were identified as the key mediators of IL-13–dependent CTGF expression. Furthermore, IL-13 induces Stat6 phosphorylation in HSCs, but Stat6 was not involved in CTGF induction. Instead, the Erk1/2-MAPK pathway was found to be responsible for IL-13–induced early Smad phosphorylation and CTGF synthesis. We demonstrate that IL-13 induces CTGF expression in HSCs by activating TGF-β–independent activin receptor-like kinase/Smad signaling via the Erk-MAPK pathway rather than via its canonical JAK/Stat6 pathway. These results provide an improved new insight into the molecular mechanisms of profibrotic IL-13 activities in the liver.

The Effector Protein BPE005 from Brucella abortus Induces Collagen Deposition and Matrix Metalloproteinase 9 Downmodulation via Transforming Growth Factor β1 in Hepatic Stellate Cells

“…Hepatic stellate cells are recognized as the main source of liver fibrosis (5). Liver fibrosis is characterized by the deposition of extracellular matrix.…”

“…An early event in the development of liver fibrosis is the activation of hepatic stellate cells (HSCs), the major cell type responsible for increased synthesis of extracellular matrix proteins (5). An elevated level of transforming growth factor ␤1 (TGF-␤1) is also observed in the damaged liver, and it has a close correlation with fibrogenic changes in HSCs and liver tissue (6)(7)(8).…”

T cell subsets and their signature cytokines in autoimmune and inflammatory diseases

“…Furthermore, these mice showed increased numbers of classically activated macrophages and decreased numbers of alternatively activated macrophages infiltrating the heart as compared with Wt mice. It must be noted, however, that IL-13 also has profibrogenic effects either directly, or through upregulation of transforming growth factor beta (TGF-β) synthesis 94 . Taken together, most of the evidence points towards a protective role for IL-13 in myocarditis by modulating macrophage populations and regulating their function 95 .…”

Molecular Mechanism and Treatment of Viral Hepatitis-Related Liver Fibrosis

“…Th1 cells release IFN-γ, reducing liver fibrogenesis by inhibiting the TGF-β-induced transduction cascade [4]. Th2 cells promote liver fibrosis by producing IL13 [44]. The number of Th17 cells, or IL17-positive lymphocytes, increases in patients with chronic hepatitis B or alcoholic liver disease and correlates with the severity of liver fibrosis [45,46].…”