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 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 Interleukin-13 augments transforming growth factor-β1-induced tissue inhibitor of metalloproteinase-1 expression in primary human airway fibroblasts

2005 ◽  
Vol 288 (2) ◽  
pp. C435-C442 ◽  
Author(s):  
XiuXia Zhou ◽  
John B. Trudeau ◽  
Kathryn J. Schoonover ◽  
Jessica I. Lundin ◽  
Steve M. Barnes ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Expression ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitor ◽  
Mrna Stabilization ◽  
Protein Levels ◽  
Human Airway ◽  
Tgf Β1

Tissue inhibitor of metalloproteinase (TIMP)-1 is a potent inhibitor of activated matrix metalloproteinases (MMPs) such as gelatinases and collagenases. TIMP-1 is induced by transforming growth factor-β1 (TGF-β1), but details regarding signaling pathways remain unclear. T-helper-2 cytokines also have profibrotic properties and can interact with TGF-β. In the present study, we examined the effects of interleukin (IL)-13 (2,500 pM) on TGF-β1 (200 pM)-induced expression of TIMP-1 mRNA and protein in primary human airway fibroblasts obtained from 57 human subjects. IL-13 alone had no effect on TIMP-1 mRNA or protein expression. However, IL-13 synergistically augmented TGF-β1-induced TIMP-1 mRNA and protein expression ( P < 0.001 vs. TGF-β1 alone). The upregulation of TIMP-1 by the combination of TGF-β1 and IL-13 involved increased transcription, with little effect on mRNA stabilization. Initial exploration of the pathways leading to the synergy determined that activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway by IL-13 may have a negative effect on TIMP-1 production. The specific PI3K inhibitor LY-294002 in the presence of TGF-β1, IL-13, or the combination of the two caused significant increases in TIMP-1 mRNA expression, while LY-294002 increased TIMP-1 protein levels in the presence of IL-13 alone. These results suggest that IL-13 augments TGF-β1-induced profibrotic responses at both the mRNA and protein levels. Although IL-13 induced activation of PI3K-Akt, the activation did not contribute to the synergy observed with TGF-β1 plus IL-13 in TIMP-1 expression and in fact may dampen it. The mechanisms behind the synergy remain to be determined.

scholarly journals Transforming Growth Factor β1 Receptor II Is Downregulated by E1A in Adenovirus-Infected Cells

2003 ◽  
Vol 77 (17) ◽  
pp. 9324-9336 ◽  
Author(s):  
Vera L. Tarakanova ◽  
William S. M. Wold
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Protein Levels ◽  
Quiescent Cells ◽  
Growth Inhibitory ◽  
Infected Cells ◽  
Cycle Regulation ◽  
Tgf Β1

ABSTRACT Transforming growth factor β1 (TGF-β1) signaling is compromised in many tumors, thereby allowing the tumor to escape the growth-inhibitory and proapoptotic activities of the cytokine. Human adenoviruses interfere with a number of cellular pathways involved in cell cycle regulation and apoptosis, initially placing the cell in a “tumor-like” state by forcing quiescent cells into the cell cycle and also inhibiting apoptosis. We report that adenovirus-infected cells resemble tumor cells in that TGF-β1 signaling is inhibited. The levels of TGF-β1 receptor II (TβRII) in adenovirus-infected cells were decreased, and this decrease was mapped, by using virus mutants, to the E1A gene and to amino acids 2 to 36 and the C-terminal binding protein binding site in the E1A protein. The decrease in the TβRII protein was accompanied by a decrease in TβRII mRNA. The decrease in TβRII protein levels in adenovirus-infected cells was greater than the decrease in TβRII mRNA, suggesting that downregulation of the TβRII protein may occur through more than one mechanism. Surprisingly in this context, the half-lives of the TβRII protein in infected and uninfected cells were similar. TGF-β1 signaling was compromised in cells infected with wild-type adenovirus, as measured with 3TP-lux, a TGF-β-sensitive reporter plasmid expressing luciferase. Adenovirus mutants deficient in TβRII downregulation did not inhibit TGF-β1 signaling. TGF-β1 pretreatment reduced the relative abundance of adenovirus structural proteins in infected cells, an effect that was potentiated when cells were infected with mutants incapable of modulating the TGF-β signaling pathway. These results raise the possibility that inhibition of TGF-β signaling by E1A is a means by which adenovirus counters the antiviral defenses of the host.

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.

scholarly journals Manipulation of the Fascial System Applied During Acute Inflammation of the Connective Tissue of the Thoracolumbar Region Affects Transforming Growth Factor-β1 and Interleukin-4 Levels: Experimental Study in Mice

2020 ◽  
Vol 11 ◽  
Author(s):  
Maria Elisa Duarte França ◽  
Larissa Sinhorim ◽  
Daniel Fernandes Martins ◽  
Robert Schleip ◽  
Nicolas A. M. M. Machado-Pereira ◽  
...  
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Transforming Growth Factor ◽  
Neutrophil Migration ◽  
Transforming Growth Factor Β1 ◽  
Interleukin 4 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Monocyte Chemoattractant Protein 1 ◽  
Thoracolumbar Region ◽  
Tgf Β1

Fascia can become rigid and assume a fibrotic pattern due to inflammatory processes. Manipulation of the fascial system (MFS), manual technique targeting connective tissues, is commonly used in clinical practice in pain management. We aimed to verify MFS effects on the connective tissue inflammatory changes in mice. Swiss Mus musculus male mice (n = 44) were distributed into groups: carrageenan without treatment (Car, n = 11), carrageenan with MFS (Car + MFS, n = 12), saline without treatment (n = 10), and saline with MFS (saline + MFS, n = 11). Interleukin 4 (IL-4), IL-6, tumor necrosis factor (TNF), transforming growth factor β1 (TGF-β1), and monocyte chemoattractant protein 1 (MCP-1) levels were verified by enzyme-linked immunosorbent assay. Neutrophil (Ly-6G), macrophage (F4/80), and nitric oxide synthase 2 (NOS-2) were identified using Western blot. The MFS protocol was applied from the first to the third day after inflammation of the connective tissue of the thoracolumbar region. There was a significant MFS effect on IL-4 (p = 0.02) and TGF-β1 (p = 0.04), without increasing MCP-1, TNF, and IL-6 levels (p &gt; 0.05) on thoracolumbar region from Car + MFS, in comparison with saline. Ly-6G in Car + MFS presented lower levels when compared with saline (p = 0.003) or saline + MFS (0.003). NOS-2 levels were lower in Car + MFS than in saline + MFS (p = 0.0195) or saline (p = 0.003). MFS may have an anti-inflammatory effect, based on TGF-β1 and IL-4. IL-4 may have inhibited neutrophil migration. Lower levels of NOS-2 may be linked to the lack of macrophages, which are responsible for NOS-2 expression.

scholarly journals Myocardial Protection by Salvia Miltiorrhiza Injection in Streptozotocin-Induced Diabetic Rats through Attenuation of Expression of Thrombospondin-1 and Transforming Growth Factor-β1

2012 ◽  
Vol 40 (3) ◽  
pp. 1016-1024 ◽  
Author(s):  
J Yu ◽  
J Fei ◽  
J Azad ◽  
M Gong ◽  
Y Lan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Heart Function ◽  
Salvia Miltiorrhiza ◽  
Transforming Growth Factor Β1 ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Pathological Changes ◽  
Protein Levels ◽  
Tgf Β1

OBJECTIVES: To investigate the myocardially protective effects of Salvia miltiorrhiza injection in streptozotocin-induced diabetic rats and the possible mechanisms involved. METHODS: Adult male Sprague—Dawley rats were randomized into three groups ( n = 10 per group): diabetes, no treatment (Sm-); diabetes, S. miltiorrhiza injection (Sm+); control (no diabetes; saline treatment). After model induction and 4 weeks' treatment, heart function of five rats from each group was tested by Langendorff isolated in vivo heart perfusion. In the remaining rats, pathological changes of the myocardium were observed by haematoxylin and eosin staining, and protein levels of thrombospondin-1 (TSP-1) and transforming growth factor-β1 (TGF-β1) were assessed by immunohistochemistry. RESULTS: Left ventricular systolic end pressure and left ventricular developed pressure were significantly improved in the Sm+ group compared with the Sm- group. Pathological changes were ameliorated through significantly reduced TSP-1 and TGF-β1 protein levels. CONCLUSIONS: S. miltiorrhiza injection may improve the heart function of diabetic rats and protect against cardiomyopathy by downregulating TSP-1 and TGF-β1 in myocardial tissue.

Abstract 058: Transforming Growth Factor β1 Antagonizes Npr1 Expression and Vascular Signaling: Role of Transcription Factor δEF1 Transforming Growth Factor β1 Antagonizes Npr1 Expression and Vascular Signaling: Role of Transcription Factor δEF1

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Anagha Sen ◽  
Prerna Kumar ◽  
Sarah H Lindsey ◽  
Prasad V Katakam ◽  
Meaghan Bloodworth ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Protein Expression ◽  
Transforming Growth Factor ◽  
Fold Increase ◽  
Transforming Growth Factor Β1 ◽  
Protein Levels ◽  
Tgf Β1

The objective of the present study was to examine the repressive effect of transforming growth factor beta 1 (TGF-β1) in the regulation of Npr1 (coding for guanylyl cyclase/natriuretic peptide receptor-A; GC-A/NPRA) gene expression and vascular signaling. The rat thoracic aortic vascular smooth muscle cells (RTASMC) and denuded aortic rings were cultured in Dulbecco’s modified Eagle’s medium containing 10% fetal bovine serum and treated with TGF-β1 in a time-and dose-dependent manner. Treatment with TGF-β1 decreased NPRA mRNA and protein levels by 62% (0.42 ± 0.05 vs. control, 0.9 ± 0.02, p < 0.01) and 55% (9603 ± 860 vs. control, 22211 ± 1449, p < 0.01), respectively. TGF-β1 treatment significantly increased delta EF1 (δEF1) protein expression by 2.4-fold (907.9 ± 36.5. vs. control, 378.5 ± 10.3; p < 0.001) and enhanced its recruitment to Npr1 promoter. TGF-β1-treated RTASMCs and denuded aortic rings showed significant increases in α-smooth muscle actin (α-SMA) and collagen type 1 alpha 2 (COL1A2) protein expression, which were markedly attenuated by ANP treatments. The TGF-β1-pretreated cells showed 2.6-fold increase in α-SMA (control, 1523 ± 143, TGF-β1, 3997 ± 182 and TGF-β1 + ANP, 2172 ± 135) and 3.4-fold increase in COL1A2 (control, 1250 ± 77, TGF-β1, 4234 ± 110 and TGF-β1 + ANP, 1546 ± 57), respectively. In ex vivo experiments of denuded-aortic rings, TGF-β1 decreased Npr1 mRNA and protein levels by 62% (0.39 ± 0.06 vs. control 1.10 ± 0.01) and 70% (2609 ± 69 vs. control 5775 ± 123), respectively, and significantly (p < 0.0) increased the expression of TGF-β1-responsive proteins, namely α-SMA (2.6-fold) and COL1A2 (3.1-fold). Treatment with increasing concentrations of ANP (IC50=6x10 -9 M), relaxed denuded aortic rings contracted with prostaglandin F2α (PGF2α); however, pretreatment with TGF-β1 significantly attenuated ANP-mediated vascular relaxation after PFG2α contraction (ANP-treated, 68.68 ± 9.4 vs. TGF-β1 + ANP-treated 88.85 ± 4.7). The endothelium-intact vessels were not affected by TGF-β1 incubation. Together, the present results suggest that an antagonistic cascade exists between TGF-β1 pathways and ANP/NPRA signaling, which might be critical in the vascular remodeling and regulation of hypertension and cardiovascular homeostasis.

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.

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