scholarly journals Rapid Up-Regulation of α4 Integrin-mediated Leukocyte Adhesion by Transforming Growth Factor-β1

2003 ◽  
Vol 14 (1) ◽  
pp. 54-66 ◽  
Author(s):  
Rubén A. Bartolomé ◽  
Francisco Sanz-Rodrı́guez ◽  
Mar M. Robledo ◽  
Andrés Hidalgo ◽  
Joaquin Teixidó
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Human Peripheral Blood ◽  
Transforming Growth Factor Β1 ◽  
Small Gtpase ◽  
Mitogen Activated Protein Kinase ◽  
Intracellular Camp ◽  
Tgf Β1

The α4 integrins (α4β1 and α4β7) are cell surface heterodimers expressed mostly on leukocytes that mediate cell-cell and cell-extracellular matrix adhesion. A characteristic feature of α4 integrins is that their adhesive activity can be subjected to rapid modulation during the process of cell migration. Herein, we show that transforming growth factor-β1 (TGF-β1) rapidly (0.5–5 min) and transiently up-regulated α4 integrin-dependent adhesion of different human leukocyte cell lines and human peripheral blood lymphocytes (PBLs) to their ligands vascular cell adhesion molecule-1 (VCAM-1) and connecting segment-1/fibronectin. In addition, TGF-β1 enhanced the α4 integrin-mediated adhesion of PBLs to tumor necrosis factor-α–treated human umbilical vein endothelial cells, indicating the stimulation of α4β1/VCAM-1 interaction. Although TGF-β1 rapidly activated the small GTPase RhoA and the p38 mitogen-activated protein kinase, enhanced adhesion did not require activation of both signaling molecules. Instead, polymerization of actin cytoskeleton triggered by TGF-β1 was necessary for α4 integrin-dependent up-regulated adhesion, and elevation of intracellular cAMP opposed this up-regulation. Moreover, TGF-β1 further increased cell adhesion mediated by α4 integrins in response to the chemokine stromal cell-derived factor-1α. These data suggest that TGF-β1 can potentially contribute to cell migration by dynamically regulating cell adhesion mediated by α4 integrins.

scholarly journals JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblast Transdifferentiation in Human Graves’ Orbital Fibroblasts

2021 ◽  
Vol 22 (6) ◽  
pp. 2952
Author(s):  
Tzu-Yu Hou ◽  
Shi-Bei Wu ◽  
Hui-Chuan Kau ◽  
Chieh-Chih Tsai
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mapk Pathway ◽  
Transforming Growth Factor Β1 ◽  
Tissue Growth ◽  
Mitogen Activated Protein Kinase ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Western Blots ◽  
Orbital Fibroblasts ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.

scholarly journals Melatonin Inhibits Transforming Growth Factor-β1-Induced Epithelial–Mesenchymal Transition in AML12 Hepatocytes

Biology ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 84 ◽  
Author(s):  
Kim ◽  
Park ◽  
Kim ◽  
Leem ◽  
Park
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Protective Action ◽  
Transforming Growth Factor Β1 ◽  
Membrane Receptors ◽  
Mitogen Activated Protein Kinase ◽  
Independent Manner ◽  
Mesenchymal Transition ◽  
Tgf Β1

Recent studies showed that melatonin, a well-known pineal hormone that modulates the circadian rhythm, exerts beneficial effects against liver fibrosis. However, mechanisms for its protective action against the fibrotic processes remain incompletely understood. Here, we aimed to explore the effects of the hormone on transforming growth factor-β1 (TGF-β1)-stimulated epithelial–mesenchymal transition (EMT) in AML12 hepatocytes. Pretreatment with melatonin dose-dependently reversed downregulation of an epithelial marker and upregulation of mesenchymal markers after TGF-β1 stimulation. Additionally, melatonin dose-dependently suppressed an increased phosphorylation of Smad2/3 after TGF-β1 treatment. Besides the canonical Smad signaling pathway, an increase in phosphorylation of extracellular signal-regulated kinase 1/2 and p38 was also dose-dependently attenuated by melatonin. The suppressive effect of the hormone on EMT stimulated by TGF-β1 was not affected by luzindole, an antagonist of melatonin membrane receptors, suggesting that its membrane receptors are not required for the inhibitory action of melatonin. Moreover, melatonin suppressed elevation of intracellular reactive oxygen species (ROS) levels in TGF-β1-treated cells. Finally, TGF-β1-stimulated EMT was also inhibited by the antioxidant N-acetylcysteine. Collectively, these results suggest that melatonin prevents TGF-β1-stimulated EMT through suppression of Smad and mitogen-activated protein kinase signaling cascades by deactivating ROS-dependent mechanisms in a membrane receptor-independent manner.

Small GTPase Rap1 regulates cell migration through regulation of small GTPase RhoA activity in response to transforming growth factor-β1

2013 ◽  
Vol 228 (11) ◽  
pp. 2119-2126 ◽  
Author(s):  
Mi-Young Moon ◽  
Hee-Jun Kim ◽  
Jae-Gyu Kim ◽  
Jae-Yong Lee ◽  
Jaebong Kim ◽  
...  
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Small Gtpase ◽  
Rhoa Activity

scholarly journals RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1569 ◽  
Author(s):  
Rabea Zinn ◽  
Hannah Otterbein ◽  
Hendrik Lehnert ◽  
Hendrik Ungefroren
Keyword(s):  
Gene Expression ◽  
Cell Migration ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Small Gtpase ◽  
Mitogen Activated Protein Kinase ◽  
Ductal Adenocarcinoma ◽  
Mesenchymal Transition ◽  
Migratory Activity ◽  
Tgf Β1

The small GTPase Ras-related C3 botulinum toxin substrate 1B (RAC1B) has been shown to potently inhibit transforming growth factor (TGF)-β1-induced cell migration and epithelial-mesenchymal transition (EMT) in pancreatic and breast epithelial cells, but the underlying mechanism has remained obscure. Using a panel of pancreatic ductal adenocarcinoma (PDAC)-derived cell lines of different differentiation stages, we show that RAC1B is more abundantly expressed in well differentiated as opposed to poorly differentiated cells. Interestingly, RNA interference-mediated knockdown of RAC1B decreased expression of the epithelial marker protein E-cadherin, encoded by CDH1, and enhanced its TGF-β1-induced downregulation, whereas ectopic overexpression of RAC1B upregulated CDH1 expression and largely prevented its TGF-β1-induced silencing of CDH1. Conversely, knockdown of RAC1B, or deletion of the RAC1B-specific exon 3b by CRISPR/Cas-mediated genomic editing, enhanced basal and TGF-β1-induced upregulation of mesenchymal markers like Vimentin, and EMT-associated transcription factors such as SNAIL and SLUG. Moreover, we demonstrate that knockout of RAC1B enhanced the cells’ migratory activity and derepressed TGF-β1-induced activation of the mitogen-activated protein kinase ERK2. Pharmacological inhibition of ERK1/2 activation in RAC1B-depleted cells rescued cells from the RAC1B knockdown-induced enhancement of cell migration, TGF-β1-induced downregulation of CDH1, and upregulation of SNAI1. We conclude that RAC1B promotes epithelial gene expression and suppresses mesenchymal gene expression by interfering with TGF-β1-induced MEK-ERK signaling, thereby protecting cells from undergoing EMT and EMT-associated responses like acquisition of cell motility.

Transforming growth factor-β1 down-regulates expression of chemokine stromal cell–derived factor-1: functional consequences in cell migration and adhesion

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 1978-1984 ◽  
Author(s):  
Natalia Wright ◽  
Teresa Laín de Lera ◽  
Carelia García-Moruja ◽  
Rosa Lillo ◽  
Félix García-Sánchez ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Migration ◽  
Growth Factor ◽  
Stromal Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Hematopoietic Progenitor ◽  
Functional Consequences ◽  
Stromal Cell Derived Factor ◽  
Tgf Β1

Abstract Chemokine stromal cell–derived factor-1 (SDF-1) is expressed by bone marrow (BM) stromal cells and plays key roles in BM cell migration. Modulation of its expression could affect the migratory capacity of cells trafficking the BM, such as hematopoietic progenitor and leukemic cells. Transforming growth factor-β1 (TGF-β1) is present in the BM environment and constitutes a pivotal molecule controlling BM cell proliferation and differentiation. We used the BM stromal cell line MS-5 as a model to investigate whether SDF-1 expression constitutes a target for TGF-β1 regulation and its functional consequences. We show here that TGF-β1 down-regulates SDF-1 expression, both at the mRNA level, involving a decrease in transcriptional efficiency, and at the protein level, as detected in lysates and supernatants from MS-5 cells. Reduction of SDF-1 in supernatants from TGF-β1–treated MS-5 cells correlated with decreased, SDF-1–dependent, chemotactic, and transendothelial migratory responses of the BM model cell lines NCI-H929 and Mo7e compared with their responses to supernatants from untreated MS-5 cells. In addition, supernatants from TGF-β1–exposed MS-5 cells had substantially lower efficiency in promoting integrin α4β1–mediated adhesion of NCI-H929 and Mo7e cells to soluble vascular cell adhesion molecule-1 (sVCAM-1) and CS-1/fibronectin than their untreated counterparts. Moreover, human cord blood CD34+ hematopoietic progenitor cells displayed SDF-1–dependent reduced responses in chemotaxis, transendothelial migration, and up-regulation of adhesion to sVCAM-1 when supernatants from TGF-β1–treated MS-5 cells were used compared with supernatants from untreated cells. These data indicate that TGF-β1–controlled reduction in SDF-1 expression influences BM cell migration and adhesion, which could affect the motility of cells trafficking the bone marrow.

Transforming growth factor-β1 regulates macrophage migration via RhoA

Blood ◽  
2006 ◽  
Vol 108 (6) ◽  
pp. 1821-1829 ◽  
Author(s):  
Jun-Sub Kim ◽  
Jae-Gyu Kim ◽  
Mi-Young Moon ◽  
Chan-Young Jeon ◽  
Ha-Young Won ◽  
...  
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Rho Gtpase ◽  
Initial Period ◽  
Transforming Growth Factor Β1 ◽  
Dominant Negative ◽  
Monocyte Chemoattractant Protein 1 ◽  
Protein Levels ◽  
Tgf Β1

Abstract Brief treatment with transforming growth factor (TGF)–β1 stimulated the migration of macrophages, whereas long-term exposure decreased their migration. Cell migration stimulated by TGF-β1 was markedly inhibited by 10 μg/mL Tat-C3 exoenzyme. TGF-β1 increased mRNA and protein levels of macrophage inflammatory protein (MIP)–1α in the initial period, and these effects also were inhibited by 10 μg/mL Tat-C3 and a dominant-negative (DN)–RhoA (N19RhoA). Cycloheximide, actinomycin D, and antibodies against MIP-1α and monocyte chemoattractant protein-1 (MCP-1) abolished the stimulation of cell migration by TGF-β1. These findings suggest that migration of these cells is regulated directly and indirectly via the expression of chemokines such as MIP-1α and MCP-1 mediated by RhoA in response to TGF-β1. TGF-β1 activated RhoA in the initial period, and thereafter inactivated them, suggesting that the inactivation of RhoA may be the cause of the reduced cell migration in response to TGF-β1 at later times. We therefore attempted to elucidate the molecular mechanism of the inactivation of RhoA by TGF-β1. First, TGF-β1 phosphorylated RhoA via protein kinase A, leading to inactivation of RhoA. Second, wild-type p190 Rho GTPase activating protein (p190RhoGAP) reduced and DN-p190RhoGAP reversed the reduction of cell migration induced by TGF-β, suggesting that it inactivated RhoA via p190 Rho GAP.

scholarly journals MEK1/2 Inhibitors Block Basal and Transforming Growth Factor β1-Stimulated JC Virus Multiplication

2007 ◽  
Vol 81 (12) ◽  
pp. 6412-6418 ◽  
Author(s):  
Veerasamy Ravichandran ◽  
Peter N. Jensen ◽  
Eugene O. Major
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Transforming Growth Factor ◽  
Jc Virus ◽  
Transforming Growth Factor Β1 ◽  
Virus Multiplication ◽  
Membrane Receptors ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Tgf Β1

ABSTRACT The multiplication of the human neurotropic polyomavirus JC virus (JCV) is regulated by cell membrane receptors and nuclear transcription factors. Signaling pathways also play a role in determining the extent to which JCV can productively infect cells. These data show that constitutively active MEK1 protein (CA-MEK1), overexpressed in cultures of human glia, supports a substantial increase in late JCV protein (Vp-1) synthesis. The specificity of this pathway was indicated by no significant enhancement of JCV multiplication through activation of other components of mitogen-activated protein kinase pathways such as p38, Jun N-terminal protein kinase, and protein kinase A. Further evidence supporting the importance of signaling in JCV infection came from addition of transforming growth factor β1 (TGF-β1), which stimulated a 200% increase of Vp-1 expression. Specific MEK1/2 inhibitors, flavenoid PD98059 and U0126, decreased the basal and TGF-β1-stimulated Vp-1 expression by 95% or more. TGF-β1 is known to phosphorylate/activate Smad DNA binding proteins that could subsequently bind or increase binding to JCV promoter sequences, linking the effects of signaling with JCV transcriptional regulation. The effectiveness with which MEK1/2 inhibitors block JCV multiplication provides insight that may contribute to development of compounds directed against JCV.

scholarly journals JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblasts Transdifferentiation in Graves' Orbital Fibroblasts

2021 ◽  
Author(s):  
Tzu-Yu Hou ◽  
Shi-Bei Wu ◽  
Hui-Chuan Kau ◽  
Chieh-Chih Tsai
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β1 ◽  
Tissue Growth ◽  
Mitogen Activated Protein Kinase ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Mapk Pathways ◽  
Orbital Fibroblasts ◽  
Tgf Β1

Abstract Transforming growth factor-β1 (TGF-β1)-induced myofibroblasts transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathway through which TGF-β1 activates Graves’ orbital fibroblasts is unclear. This study investigated the role of mitogen-activated protein kinase (MAPK) pathways in TGF-β1-induced myofibroblasts transdifferentiation of Graves’ orbital fibroblasts. MAPK pathways were assessed by measuring the phosphorylation levels of p38, c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) using Western blot analysis. The expression levels of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), fibronectin, and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-3) representing fibrogenesis processes were analysed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of MAPK pathways. After treating Graves’ orbital fibroblasts with TGF-β1, the phosphorylation levels of p38 and JNK but not ERK were increased. Meanwhile, CTGF, α-SMA and fibronectin were overexpressed. After pre-incubation with p38, JNK and ERK inhibitors respectively, the TGF-β1-induced expression of CTGF, α-SMA, fibronectin, TIMP-1 and TIMP3 was abolished by p38 and JNK inhibitors but not ERK inhibitors. This study confirmed TGF-β1-induced myofibroblasts transdifferentiation in Graves' orbital fibroblasts via p38 and JNK signaling. Thus, MAPK pathways may be potential targets for the management of GO.

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