scholarly journals Mechanisms of induction of airway smooth muscle hyperplasia by transforming growth factor-β

2007 ◽  
Vol 293 (1) ◽  
pp. L245-L253 ◽  
Author(s):  
Shaoping Xie ◽  
Maria B. Sukkar ◽  
Razao Issa ◽  
Nadia M. Khorasani ◽  
Kian Fan Chung
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
P38 Mapk ◽  
Airway Smooth Muscle ◽  
Transforming Growth Factor ◽  
Dominant Negative ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Mitogenic Signaling ◽  
Tgf Β1

Airway smooth muscle (ASM) hyperplasia is a characteristic feature of the asthmatic airway, but the underlying mechanisms that induce ASM hyperplasia remain unknown. Because transforming growth factor (TGF)-β is a potent regulator of ASM cell proliferation, we determined its expression and mitogenic signaling pathways in ASM cells. We obtained ASM cells by laser capture microdissection of bronchial biopsies and found that ASM cells from asthmatic patients expressed TGF-β1 mRNA and protein to a greater extent than nonasthmatic individuals using real-time RT-PCR and immunohistochemistry, respectively. TGF-β1 stimulated the growth of nonconfluent and confluent ASM cells either in the presence or absence of serum in a time- and concentration-dependent manner. The mitogenic activity of TGF-β1 on ASM cells was inhibited by selective inhibitors of TGF-β receptor I kinase (SD-208), phosphatidylinositol 3-kinase (PI3K, LY-294002), ERK (PD-98059), JNK (SP-600125), and NF-κB (AS-602868). On the other hand, p38 MAPK inhibitor (SB-203580) augmented TGF-β1-induced proliferation. To study role of the Smads, we transduced ASM cells with an adenovirus vector-expressing Smad4, Smad7, or dominant-negative Smad3 and found no involvement of these Smads in TGF-β1-induced proliferation. Dexamethasone caused a dose-dependent inhibition in TGF-β1-induced proliferation. Our findings suggest that TGF-β1 may act in an autocrine fashion to induce ASM hyperplasia, mediated by its receptor and several kinases including PI3K, ERK, and JNK, whereas p38 MAPK is a negative regulator. NF-κB is also involved in the TGF-β1 mitogenic signaling, but Smad pathway does not appear important.

TGF-β1 stimulates IL-8 release, COX-2 expression, and PGE2release in human airway smooth muscle cells

2000 ◽  
Vol 279 (1) ◽  
pp. L201-L207 ◽  
Author(s):  
Choong Yi Fong ◽  
Linhua Pang ◽  
Elaine Holland ◽  
Alan J. Knox
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Transforming Growth Factor ◽  
Airway Smooth Muscle Cells ◽  
Dependent Manner ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Tgf Β1

We have recently shown that endogenous prostanoids are critical in bradykinin-stimulated interleukin (IL)-8 release from human airway smooth muscle (ASM) cells. In this study, we tested the ability of transforming growth factor (TGF)-β1 to stimulate IL-8 release, cyclooxygenase (COX)-2 expression and PGE2 generation in cultured human ASM cells and explored the role of COX products and COX-2 induction on IL-8 release. TGF-β1 stimulated IL-8 release, COX-2 induction, and PGE2 generation in a concentration- and time-dependent manner. Maximal IL-8 release was achieved with 10 ng/ml of TGF-β1 after 16 h of incubation, which was inhibited by the transcription inhibitor actinomycin D and the corticosteroid dexamethasone but was not affected by the nonselective COX inhibitor indomethacin and the selective COX-2 inhibitor NS-398 despite their inhibition on TGF-β1-induced PGE2 release. These results show for the first time that TGF-β1 stimulates IL-8 release, COX-2 induction, and PGE2 generation in human ASM cells and that PGE2 generation is not critical for TGF-β1-induced IL-8 release. These findings suggest that TGF-β1 may play an important role in the pathophysiology of asthma.

scholarly journals IGFBP-3 mediates TGF-β1-induced cell growth in human airway smooth muscle cells

2000 ◽  
Vol 278 (3) ◽  
pp. L545-L551 ◽  
Author(s):  
Pinchas Cohen ◽  
Roopmathy Rajah ◽  
Joel Rosenbloom ◽  
David J. Herrick
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Cell Growth ◽  
Airway Smooth Muscle ◽  
Transforming Growth Factor ◽  
Airway Smooth Muscle Cells ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
Tgf Β1 ◽  
Igfbp 3

Both insulin-like growth factor binding protein-3 (IGFBP-3) and transforming growth factor-β (TGF-β) have been separately shown to have cell-specific growth-inhibiting or growth-potentiating effects. TGF-β stimulates IGFBP-3 mRNA and peptide expression in several cell types, and TGF-β-induced growth inhibition and apoptosis have been shown to be mediated through the induction of IGFBP-3. However, a link between the growth stimulatory effects of TGF-β and IGFBP-3-induction has not been shown. In this study, we investigated the role of IGFBP-3 in mediating TGF-β1-induced cell growth using human airway smooth muscle (ASM) cells as our model. TGF-β1 (1 ng/ml) treatment induced a 10- to 20-fold increase in the levels of expression of IGFBP-3 mRNA and protein. Addition of either IGFBP-3 or TGF-β1 to the growth medium resulted in an approximately twofold increase in cell proliferation. Coincubation of ASM cells with IGFBP-3 antisense (but not sense) oligomers as well as with an IGFBP-3 neutralizing antibody (but not with control IgG) blocked the growth induced by TGF-β1 ( P < 0.001). Several IGFBP-3-associated proteins were observed in ASM cell lysates, which may have a role in the cellular responses to IGFBP-3. These findings demonstrate that IGFBP-3 is capable of mediating the growth stimulatory effect of TGF-β in ASM cells.

scholarly journals Transforming growth factor (TGF)-β1-induced miR-133a inhibits myofibroblast differentiation and pulmonary fibrosis

2019 ◽  
Vol 10 (9) ◽  
Author(s):  
Peng Wei ◽  
Yan Xie ◽  
Peter W. Abel ◽  
Yapei Huang ◽  
Qin Ma ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Tissue Growth ◽  
Negative Regulator ◽  
Lung Fibroblasts ◽  
Luciferase Reporter ◽  
Myofibroblast Differentiation ◽  
Dependent Manner ◽  
Tgf Β1

Abstract Transforming growth factor (TGF)-β1, a main profibrogenic cytokine in the progression of idiopathic pulmonary fibrosis (IPF), induces differentiation of pulmonary fibroblasts to myofibroblasts that produce high levels of collagen, leading to concomitantly loss of lung elasticity and function. Recent studies implicate the importance of microRNAs (miRNAs) in IPF but their regulation and individual pathological roles remain largely unknown. We used both RNA sequencing and quantitative RT-PCR strategies to systematically study TGF-β1-induced alternations of miRNAs in human lung fibroblasts (HFL). Our data show that miR-133a was significantly upregulated by TGF-β1 in a time- and concentration-dependent manner. Surprisingly, miR-133a inhibits TGF-β1-induced myofibroblast differentiation whereas miR-133a inhibitor enhances TGF-β1-induced myofibroblast differentiation. Interestingly, quantitative proteomics analysis indicates that miR-133a attenuates myofibroblast differentiation via targeting multiple components of TGF-β1 profibrogenic pathways. Western blot analysis confirmed that miR-133a down-regulates TGF-β1-induced expression of classic myofibroblast differentiation markers such as ɑ-smooth muscle actin (ɑ-SMA), connective tissue growth factor (CTGF) and collagens. miRNA Target Searcher analysis and luciferase reporter assays indicate that TGF-β receptor 1, CTGF and collagen type 1-alpha1 (Col1a1) are direct targets of miR-133a. More importantly, miR-133a gene transferred into lung tissues ameliorated bleomycin-induced pulmonary fibrosis in mice. Together, our study identified TGF-β1-induced miR-133a as an anti-fibrotic factor. It functions as a feed-back negative regulator of TGF-β1 profibrogenic pathways. Thus, manipulations of miR-133a expression may provide a new therapeutic strategy to halt and perhaps even partially reverse the progression of IPF.

TAK1 plays a major role in growth factor-induced phenotypic modulation of airway smooth muscle

2011 ◽  
Vol 301 (5) ◽  
pp. L822-L828 ◽  
Author(s):  
Tonio Pera ◽  
Riham Sami ◽  
Johan Zaagsma ◽  
Herman Meurs
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Dna Synthesis ◽  
Airway Smooth Muscle ◽  
Transforming Growth Factor ◽  
Airway Remodeling ◽  
Dominant Negative ◽  
Tracheal Smooth Muscle ◽  
Phenotypic Modulation

Increased airway smooth muscle (ASM) mass is a major feature of airway remodeling in asthma and chronic obstructive pulmonary disease. Growth factors induce a proliferative ASM phenotype, characterized by an increased proliferative state and a decreased contractile protein expression, reducing contractility of the muscle. Transforming growth factor-β-activated kinase 1 (TAK1), a mitogen-activated protein kinase kinase kinase, is a key enzyme in proinflammatory signaling in various cell types; however, its function in ASM is unknown. The aim of this study was to investigate the role of TAK1 in growth factor-induced phenotypic modulation of ASM. Using bovine tracheal smooth muscle (BTSM) strips and cells, as well as human tracheal smooth muscle cells, we investigated the role of TAK1 in growth factor-induced proliferation and hypocontractility. Platelet-derived growth factor- (PDGF; 10 ng/ml) and fetal bovine serum (5%)-induced increases in DNA synthesis and cell number in bovine and human cells were significantly inhibited by pretreatment with the specific TAK1 inhibitor LL-Z-1640-2 (5 Z-7-oxozeaenol; 100 nM). PDGF-induced DNA synthesis and extracellular signal-regulated kinase-1/2 phosphorylation in BTSM cells were strongly inhibited by both LL-Z-1640-2 pretreatment and transfection of dominant-negative TAK1. In addition, LL-Z-1640-2 inhibited PDGF-induced reduction of BTSM contractility and smooth muscle α-actin expression. The data indicate that TAK1 plays a major role in growth factor-induced phenotypic modulation of ASM.

Abstract 297: Cyclic GMP Reduces Vascular Smooth Muscle Migration through Inhibition of TGF-ß1/Smad Signaling

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Jackson R Vuncannon ◽  
Joshua D Stone ◽  
Danielle N Martin ◽  
Chintamani N Joshi ◽  
Shaquria P Adderley ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Vascular Smooth Muscle ◽  
Cyclic Gmp ◽  
Transforming Growth Factor ◽  
Soluble Guanylate Cyclase ◽  
Sandwich Elisa ◽  
Cell Lysates ◽  
Tgf Β1

Abnormal vascular smooth muscle (VSM) growth remains an elemental foundation of vasculoproliferative disorders including atherosclerosis and restenosis. Many second messenger, cytokine, and growth factor signals mediate control of VSM growth, and among these is transforming growth factor (TGF)-β1, a pluripotent cytokine with wide-ranging yet often opposite effects in VSM. Cyclic nucleotide signaling also exerts powerful growth control of VSM, and our previous work has helped establish a biological link between cyclic GMP and TGF-β1 in injured carotid arteries. The current study characterized the influence of cyclic GMP on TGF-β1 and its receptor-activated Smad3 in rat primary VSM cells. The heme-dependent soluble guanylate cyclase (sGC) stimulator BAY 41-2272 (BAY41) significantly increased cyclic GMP and site-specific phosphorylation of vasodilator-activated serum phosphoprotein (VASP) in manner indicative of active protein kinase G (PKG) and PKA signaling. Recombinant TGF-β1 (10 ng/ml) significantly stimulated phospho-Smad3 (Ser 423/425 ) and decreased inhibitory Smad7 in VSM cell homogenates, and using flow cytometry significantly increased cells in G 2 /M and expression of cyclins D and E and Cdk2 and Cdk4 while decreasing expression of inhibitory p21 and p27 after 24 hours compared to vehicle controls. TGF-β1 also significantly increased cell numbers compared to controls after 48 hours, thus confirming growth promoting capacities of TGF-β1 in VSM. In cell lysates double-sandwich ELISA revealed that BAY41 significantly reduces total and active TGF-β1, and Western analyses showed it significantly decreases total and phospho-Smad3 Ser423/425 expression and reduces MMP-2 and MMP-9 expression and activity (via column zymography) in both cell lysates and conditioned media after 1 and 48 hours. BAY41 also significantly reduced serum- and PDGF-stimulated cell migration between 6 and 18 hours using an in vitro scrape injury and a transwell assay. In comparison, inclusive effects of BAY41 were replicated by its prototype YC-1 and by the heme-independent sGC activator BAY 60-2770. These data clearly support growth protective capacities of cGMP in VSM and propose it operates through attenuation of TGF-β1/Smad3 signaling.

scholarly journals Calcium Input Potentiates the Transforming Growth Factor (TGF)-β1-dependent Signaling to Promote the Export of Inorganic Pyrophosphate by Articular Chondrocyte

2011 ◽  
Vol 286 (22) ◽  
pp. 19215-19228 ◽  
Author(s):  
Frederic Cailotto ◽  
Pascal Reboul ◽  
Sylvie Sebillaud ◽  
Patrick Netter ◽  
Jean-Yves Jouzeau ◽  
...  
Keyword(s):  
Growth Factor ◽  
Promoter Activity ◽  
Transforming Growth Factor ◽  
Articular Chondrocytes ◽  
Specific Protein ◽  
Dependent Manner ◽  
Articular Chondrocyte ◽  
Experimental Conditions ◽  
Inorganic Pyrophosphate ◽  
Tgf Β1

Transforming growth factor (TGF)-β1 stimulates extracellular PPi (ePPi) generation and promotes chondrocalcinosis, which also occurs secondary to hyperparathyroidism-induced hypercalcemia. We previously demonstrated that ANK was up-regulated by TGF-β1 activation of ERK1/2 and Ca2+-dependent protein kinase C (PKCα). Thus, we investigated mechanisms by which calcium could affect ePPi metabolism, especially its main regulating proteins ANK and PC-1 (plasma cell membrane glycoprotein-1). We stimulated articular chondrocytes with TGF-β1 under extracellular (eCa2+) or cytosolic Ca2+ (cCa2+) modulations. We studied ANK, PC-1 expression (quantitative RT-PCR, Western blotting), ePPi levels (radiometric assay), and cCa2+ input (fluorescent probe). Voltage-operated Ca2+-channels (VOC) and signaling pathways involved were investigated with selective inhibitors. Finally, Ank promoter activity was evaluated (gene reporter). TGF-β1 elevated cCa2+ and ePPi levels (by up-regulating Ank and PC-1 mRNA/proteins) in an eCa2+ dose-dependent manner. TGF-β1 effects were suppressed by cCa2+ chelation or L- and T-VOC blockade while being mostly reproduced by ionomycin. In the same experimental conditions, the activation of Ras, the phosphorylation of ERK1/2 and PKCα, and the stimulation of Ank promoter activity were affected similarly. Activation of SP1 (specific protein 1) and ELK-1 (Ets-like protein-1) transcription factors supported the regulatory role of Ca2+. SP1 or ELK-1 overexpression or blockade experiments demonstrated a major contribution of ELK-1, which acted synergistically with SP1 to activate Ank promoter in response to TGF-β1. TGF-β1 promotes input of eCa2+ through opening of L- and T-VOCs, to potentiate ERK1/2 and PKCα signaling cascades, resulting in an enhanced activation of Ank promoter and ePPi production in chondrocyte.

scholarly journals Role of the latent TGF-beta binding protein in the activation of latent TGF-beta by co-cultures of endothelial and smooth muscle cells.

1993 ◽  
Vol 120 (4) ◽  
pp. 995-1002 ◽  
Author(s):  
R Flaumenhaft ◽  
M Abe ◽  
Y Sato ◽  
K Miyazono ◽  
J Harpel ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Muscle Cells ◽  
Beta Activity ◽  
Dependent Manner ◽  
Tgf Beta

Transforming growth factor beta (TGF-beta) is released from cells in a latent form consisting of the mature growth factor associated with an aminoterminal propeptide and latent TGF-beta binding protein (LTBP). The endogenous activation of latent TGF-beta has been described in co-cultures of endothelial and smooth muscle cells. However, the mechanism of this activation remains unknown. Antibodies to native platelet LTBP and to a peptide fragment of LTBP inhibit in a dose-dependent manner the activation of latent TGF-beta normally observed when endothelial cells are cocultured with smooth muscle cells. Inhibition of latent TGF-beta activation was also observed when cells were co-cultured in the presence of an excess of free LTBP. These data represent the first demonstration of a function for the LTBP in the extracellular regulation of TGF-beta activity and indicate that LTBP participates in the activation of latent TGF-beta, perhaps by concentrating the latent growth factor on the cell surface where activation occurs.

scholarly journals An Essential Role of the Jak-2/STAT-3/Cytosolic Phospholipase A2Axis in Platelet-derived Growth Factor BB-induced Vascular Smooth Muscle Cell Motility

2004 ◽  
Vol 279 (44) ◽  
pp. 46122-46128 ◽  
Author(s):  
Indira Neeli ◽  
Zhimin Liu ◽  
Nagadhara Dronadula ◽  
Z. Alex Ma ◽  
Gadiparthi N. Rao
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Dominant Negative ◽  
Platelet Derived Growth Factor ◽  
Dominant Negative Mutant ◽  
Dependent Manner ◽  
Cytosolic Phospholipase ◽  
Negative Mutant

Platelet-derived growth factor-BB (PDGF-BB) is a potent motogen for vascular smooth muscle cells (VSMCs). To understand its motogenic signaling events, we have studied the role of the Janus-activated kinase/signal transducers and activators of transcription (Jak/STAT) pathway and cytosolic phospholipase A2(cPLA2). PDGF-BB stimulated tyrosine phosphorylation of Jak-2 and STAT-3 in a time-dependent manner in VSMCs. In addition, AG490 and Jak-2KEpRK5, a selective pharmacological inhibitor and a dominant negative mutant, respectively, of Jak-2, attenuated PDGF-BB-induced STAT-3 tyrosine phosphorylation and its DNA binding and reporter gene activities. PDGF-BB induced VSMC motility in a dose-dependent manner with a maximum effect at 10 ng/ml. Dominant negative mutant-dependent suppression of Jak-2 and STAT-3 blocked PDGF-BB-induced VSMC motility. PDGF-BB induced the expression of cPLA2in a Jak-2/STAT-3-dependent manner, and pharmacological inhibitors of cPLA2prevented PDGFBB-induced VSMC motility. Furthermore, either exogenous addition of arachidonic acid or forced expression of cPLA2rescued PDGF-BB-induced VSMC motility from inhibition by blockade of Jak-2 and STAT-3 activation. Together, these results for the first time show that PDGF-BB-induced VSMC motility requires activation of the Jak-2/STAT-3/cPLA2signaling axis.

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