The most severe forms of type I autoimmune hepatitis are associated with genetically determined levels of TGF-β1

2010 ◽  
Vol 134 (3) ◽  
pp. 305-312 ◽  
Author(s):  
Natalia Paladino ◽  
Ana Claudia Flores ◽  
Hugo Fainboim ◽  
Teresa Schroder ◽  
Miriam Cuarterolo ◽  
...  
Keyword(s):  
Autoimmune Hepatitis ◽  
Type I ◽  
Genetically Determined ◽  
Tgf Β1

scholarly journals Proline-rich tyrosine kinase 2 mediates transforming growth factor-beta-induced hepatic stellate cell activation and liver fibrosis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jonghwa Kim ◽  
Wonseok Kang ◽  
So Hee Kang ◽  
Su Hyun Park ◽  
Ji Young Kim ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Tyrosine Kinase ◽  
Focal Adhesion ◽  
Transforming Growth Factor ◽  
Family Members ◽  
Type I ◽  
Tyrosine Kinase 2 ◽  
The Impact ◽  
Tgf Β1

AbstractHepatic fibrogenesis is characterized by activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix (ECM). The impact of ECM on TGF-β-mediated fibrogenic signaling pathway in HSCs has remained obscure. We studied the role of non-receptor tyrosine kinase focal adhesion kinase (FAK) family members in TGF-β-signaling in HSCs. We used a CCl4-induced liver fibrosis mice model to evaluate the effect of FAK family kinase inhibitors on liver fibrosis. RT-PCR and Western blot were used to measure the expression of its target genes; α-SMA, collagen, Nox4, TGF-β1, Smad7, and CTGF. Pharmacological inhibitors, siRNA-mediated knock-down, and plasmid-based overexpression were adopted to modulate the function and the expression level of proteins. Association of PYK2 activation with liver fibrosis was confirmed in liver samples from CCl4-treated mice and patients with significant fibrosis or cirrhosis. TGF-β treatment up-regulated expression of α-SMA, type I collagen, NOX4, CTGF, TGF-β1, and Smad7 in LX-2 cells. Inhibition of FAK family members suppressed TGF-β-mediated fibrogenic signaling. SiRNA experiments demonstrated that TGF-β1 and Smad7 were upregulated via Smad-dependent pathway through FAK activation. In addition, CTGF induction was Smad-independent and PYK2-dependent. Furthermore, RhoA activation was essential for TGF-β-mediated CTGF induction, evidenced by using ROCK inhibitor and dominant negative RhoA expression. We identified that TGF-β1-induced activation of PYK2-Src-RhoA triad leads to YAP/TAZ activation for CTGF induction in liver fibrosis. These findings provide new insights into the role of focal adhesion molecules in liver fibrogenesis, and targeting PYK2 may be an attractive target for developing novel therapeutic strategies for the treatment of liver fibrosis.

scholarly journals Activation of transmembrane receptor tyrosine kinase DDR1-STAT3 cascade by extracellular matrix remodeling promotes liver metastatic colonization in uveal melanoma

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Wei Dai ◽  
Shenglan Liu ◽  
Shubo Wang ◽  
Li Zhao ◽  
Xiao Yang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Cells ◽  
Uveal Melanoma ◽  
Specific Inhibitor ◽  
Type I ◽  
Matrix Remodeling ◽  
Metastatic Colonization ◽  
Tgf Β1

AbstractColonization is believed a rate-limiting step of metastasis cascade. However, its underlying mechanism is not well understood. Uveal melanoma (UM), which is featured with single organ liver metastasis, may provide a simplified model for realizing the complicated colonization process. Because DDR1 was identified to be overexpressed in UM cell lines and specimens, and abundant pathological deposition of extracellular matrix collagen, a type of DDR1 ligand, was noted in the microenvironment of liver in metastatic patients with UM, we postulated the hypothesis that DDR1 and its ligand might ignite the interaction between UM cells and their surrounding niche of liver thereby conferring strengthened survival, proliferation, stemness and eventually promoting metastatic colonization in liver. We tested this hypothesis and found that DDR1 promoted these malignant cellular phenotypes and facilitated metastatic colonization of UM in liver. Mechanistically, UM cells secreted TGF-β1 which induced quiescent hepatic stellate cells (qHSCs) into activated HSCs (aHSCs) which secreted collagen type I. Such a remodeling of extracellular matrix, in turn, activated DDR1, strengthening survival through upregulating STAT3-dependent Mcl-1 expression, enhancing stemness via upregulating STAT3-dependent SOX2, and promoting clonogenicity in cancer cells. Targeting DDR1 by using 7rh, a specific inhibitor, repressed proliferation and survival in vitro and in vivo outgrowth. More importantly, targeting cancer cells by pharmacological inactivation of DDR1 or targeting microenvironmental TGF-β1-collagen I loop exhibited a prominent anti-metastasis effect in mice. In conclusion, targeting DDR1 signaling and TGF-β signaling may be a novel approach to diminish hepatic metastasis in UM.

scholarly journals Autocrine Transforming Growth Factor-β1 Activation Mediated by Integrin αVβ3 Regulates Transcriptional Expression of Laminin-332 in Madin-Darby Canine Kidney Epithelial Cells

2010 ◽  
Vol 21 (21) ◽  
pp. 3654-3668 ◽  
Author(s):  
Jose V. Moyano ◽  
Patricia G. Greciano ◽  
Mary M. Buschmann ◽  
Manuel Koch ◽  
Karl S. Matlin
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Integrin Αvβ3 ◽  
Type I ◽  
Madin Darby Canine Kidney ◽  
Epithelial Regeneration ◽  
Tgf Β1 ◽  
Darby Canine Kidney ◽  
Canine Kidney

Laminin (LM)-332 is an extracellular matrix protein that plays a structural role in normal tissues and is also important in facilitating recovery of epithelia from injury. We have shown that expression of LM-332 is up-regulated during renal epithelial regeneration after ischemic injury, but the molecular signals that control expression are unknown. Here, we demonstrate that in Madin-Darby canine kidney (MDCK) epithelial cells LM-332 expression occurs only in subconfluent cultures and is turned-off after a polarized epithelium has formed. Addition of active transforming growth factor (TGF)-β1 to confluent MDCK monolayers is sufficient to induce transcription of the LM α3 gene and LM-332 protein expression via the TGF-β type I receptor (TβR-I) and the Smad2–Smad4 complex. Significantly, we show that expression of LM-332 in MDCK cells is an autocrine response to endogenous TGF-β1 secretion and activation mediated by integrin αVβ3 because neutralizing antibodies block LM-332 production in subconfluent cells. In confluent cells, latent TGF-β1 is secreted apically, whereas TβR-I and integrin αVβ3 are localized basolaterally. Disruption of the epithelial barrier by mechanical injury activates TGF-β1, leading to LM-332 expression. Together, our data suggest a novel mechanism for triggering the production of LM-332 after epithelial injury.

scholarly journals Estrogen induces apoptosis in a rat prostatic adenocarcinoma: Association with an increased expression of TGF- β1 and its type-I and type-II receptors

1996 ◽  
Vol 67 (4) ◽  
pp. 573-579 ◽  
Author(s):  
Maréne Landström ◽  
Solveig Eklöv ◽  
Pascal Colosetti ◽  
Sten Nilsson ◽  
Jan-Erik Damber ◽  
...  
Keyword(s):  
Prostatic Adenocarcinoma ◽  
Type I ◽  
Type Ii ◽  
Tgf Β1

Impairment of TGF-β signaling in T cells increases susceptibility to experimental autoimmune hepatitis in mice

2003 ◽  
Vol 284 (3) ◽  
pp. G525-G535 ◽  
Author(s):  
Christoph Schramm ◽  
Martina Protschka ◽  
Heinz H. Köhler ◽  
Jürgen Podlech ◽  
Matthias J. Reddehase ◽  
...  
Keyword(s):  
T Cells ◽  
Transgenic Mice ◽  
Autoimmune Hepatitis ◽  
Mononuclear Cells ◽  
Dominant Negative ◽  
Wild Type ◽  
Histological Score ◽  
Tgf Β1 ◽  
Increased Susceptibility ◽  
Experimental Autoimmune

In autoimmune hepatitis, strong TGF-β1 expression is found in the inflamed liver. TGF-β overexpression may be part of a regulatory immune response attempting to suppress autoreactive T cells. To test this hypothesis, we determined whether impairment of TGF-β signaling in T cells leads to increased susceptibility to experimental autoimmune hepatitis (EAH). Transgenic mice of strain FVB/N were generated expressing a dominant-negative TGF-β type II receptor in T cells under the control of the human CD2 promoter/locus control region. On induction of EAH, transgenic mice showed markedly increased portal and periportal leukocytic infiltrations with hepatocellular necroses compared with wild-type mice (median histological score = 1.8 ± 0.26 vs. 0.75 ± 0.09 in wild-type mice; P < 0.01). Increased IFN-γ production (118 vs. 45 ng/ml) and less IL-4 production (341 vs. 1,256 pg/ml) by mononuclear cells isolated from transgenic livers was seen. Impairment of TGF-β signaling in T cells therefore leads to increased susceptibility to EAH in mice. This suggests an important role for TGF-β in immune homeostasis in the liver and may teleologically explain TGF-β upregulation in response to T cell-mediated liver injury.

scholarly journals Matrix metalloproteinase-9 activates TGF-β and stimulates fibroblast contraction of collagen gels

2014 ◽  
Vol 306 (11) ◽  
pp. L1006-L1015 ◽  
Author(s):  
Tetsu Kobayashi ◽  
HuiJung Kim ◽  
Xiangde Liu ◽  
Hisatoshi Sugiura ◽  
Tadashi Kohyama ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Human Fibroblasts ◽  
Matrix Metalloproteinase 9 ◽  
Lung Fibroblasts ◽  
Type I ◽  
Image Analysis System ◽  
Collagen Gels ◽  
3D Collagen ◽  
Metalloproteinase 9 ◽  
Tgf Β1

Matrix metalloproteinase-9 (MMP-9) is a matrix-degrading enzyme implicated in many biological processes, including inflammation. It is produced by many cells, including fibroblasts. When cultured in three-dimensional (3D) collagen gels, fibroblasts contract the surrounding matrix, a function that is thought to model the contraction that characterizes both normal wound repair and fibrosis. The current study was designed to evaluate the role of endogenously produced MMP-9 in fibroblast contraction of 3D collagen gels. Fibroblasts from mice lacking expression of MMP-9 and human lung fibroblasts (HFL-1) transfected with MMP-9 small-interfering RNA (siRNA) were used. Fibroblasts were cast into type I collagen gels and floated in culture medium with or without transforming growth factor (TGF)-β1 for 5 days. Gel size was determined daily using an image analysis system. Gels made from MMP-9 siRNA-treated human fibroblasts contracted less than control fibroblasts, as did fibroblasts incubated with a nonspecific MMP inhibitor. Similarly, fibroblasts cultured from MMP-9-deficient mice contracted gels less than did fibroblasts from control mice. Transfection of the MMP-9-deficient murine fibroblasts with a vector expressing murine MMP-9 restored contractile activity to MMP-9-deficient fibroblasts. Inhibition of MMP-9 reduced active TGF-β1 and reduced several TGF-β1-driven responses, including activity of a Smad3 reporter gene and production of fibronectin. Because TGF-β1 also drives fibroblast gel contraction, this suggests the mechanism for MMP-9 regulation of contraction is through the generation of active TGF-β1. This study provides direct evidence that endogenously produced MMP-9 has a role in regulation of tissue contraction of 3D collagen gels mediated by fibroblasts.

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