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

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 (5Z-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.

[1]  J. Ninomiya-Tsuji,et al.  Ablation of TAK1 upregulates reactive oxygen species and selectively kills tumor cells. , 2010, Cancer research.

[2]  R. Gosens,et al.  Cigarette smoke and lipopolysaccharide induce a proliferative airway smooth muscle phenotype , 2010, Respiratory research.

[3]  C. Fortin,et al.  Constitutive Association of TGF-β–Activated Kinase 1 with the IκB Kinase Complex in the Nucleus and Cytoplasm of Human Neutrophils and Its Impact on Downstream Processes , 2010, The Journal of Immunology.

[4]  D. Postma,et al.  TLR‐related pathway analysis: novel gene–gene interactions in the development of asthma and atopy , 2010, Allergy.

[5]  R. Gosens,et al.  Airway structural components drive airway smooth muscle remodeling in asthma. , 2009, Proceedings of the American Thoracic Society.

[6]  H. Sakurai,et al.  TAK1-Mediated Serine/Threonine Phosphorylation of Epidermal Growth Factor Receptor via p38/Extracellular Signal-Regulated Kinase: NF-κB-Independent Survival Pathways in Tumor Necrosis Factor Alpha Signaling , 2009, Molecular and Cellular Biology.

[7]  Min Xie,et al.  TAK1 is an essential regulator of BMP signalling in cartilage , 2009, The EMBO journal.

[8]  S. Roscioni,et al.  Pharmacology of airway smooth muscle proliferation. , 2008, European journal of pharmacology.

[9]  Andrei V Bakin,et al.  TAK1 is required for TGF-β1-mediated regulation of matrix metalloproteinase-9 and metastasis , 2007, Oncogene.

[10]  A. Halayko,et al.  Insulin increases the expression of contractile phenotypic markers in airway smooth muscle. , 2007, American journal of physiology. Cell physiology.

[11]  H. Meurs,et al.  Extracellular matrix proteins differentially regulate airway smooth muscle phenotype and function. , 2007, American journal of physiology. Lung cellular and molecular physiology.

[12]  H. Tsukamoto,et al.  Iron Causes Interactions of TAK1, p21ras, and Phosphatidylinositol 3-Kinase in Caveolae to Activate IκB Kinase in Hepatic Macrophages* , 2007, Journal of Biological Chemistry.

[13]  Yasushi Ito,et al.  Role of RhoA inactivation in reduced cell proliferation of human airway smooth muscle by simvastatin. , 2006, American journal of respiratory cell and molecular biology.

[14]  S. Akira,et al.  TAK1 is indispensable for development of T cells and prevention of colitis by the generation of regulatory T cells. , 2006, International immunology.

[15]  Michael D. Schneider,et al.  The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function , 2006, Nature Immunology.

[16]  M. O’Connor,et al.  The TGFβ activated kinase TAK1 regulates vascular development in vivo , 2006 .

[17]  T. Kita,et al.  Activation of TGF-β1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats , 2006 .

[18]  Ki-Young Lee,et al.  TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. , 2005, Genes & development.

[19]  S. Akira,et al.  Essential function for the kinase TAK1 in innate and adaptive immune responses , 2005, Nature Immunology.

[20]  A. Vaidya,et al.  Molecular mechanisms behind the dose-dependent differential activation of MAPK pathways induced by transforming growth factor-beta1 in hematopoietic cells. , 2004, Stem cells and development.

[21]  V. Kale,et al.  Differential activation of MAPK signaling pathways by TGF-beta1 forms the molecular mechanism behind its dose-dependent bidirectional effects on hematopoiesis. , 2004, Stem cells and development.

[22]  P. Woodruff,et al.  Hyperplasia of smooth muscle in mild to moderate asthma without changes in cell size or gene expression. , 2004, American journal of respiratory and critical care medicine.

[23]  Kunihiro Matsumoto,et al.  Role of the TAK1-NLK-STAT3 pathway in TGF-β-mediated mesoderm induction , 2004 .

[24]  R. Gosens,et al.  Role of Rho-kinase in maintaining airway smooth muscle contractile phenotype. , 2004, European journal of pharmacology.

[25]  J. Ninomiya-Tsuji,et al.  A Resorcylic Acid Lactone, 5Z-7-Oxozeaenol, Prevents Inflammation by Inhibiting the Catalytic Activity of TAK1 MAPK Kinase Kinase* , 2003, The Journal of Biological Chemistry.

[26]  M. O’Connor,et al.  Expression of TAK1, a mediator of TGF-beta and BMP signaling, during mouse embryonic development. , 2003, Gene expression patterns : GEP.

[27]  R. Gosens,et al.  Muscarinic M3-receptors mediate cholinergic synergism of mitogenesis in airway smooth muscle. , 2003, American journal of respiratory cell and molecular biology.

[28]  J. Ninomiya-Tsuji,et al.  Targeted disruption of the Tab1 gene causes embryonic lethality and defects in cardiovascular and lung morphogenesis , 2002, Mechanisms of Development.

[29]  R. Gosens,et al.  Functional characterization of serum‐ and growth factor‐induced phenotypic changes in intact bovine tracheal smooth muscle , 2002, British journal of pharmacology.

[30]  D. Brenner,et al.  Dominant-negative TAK1 induces c-Myc and G(0) exit in liver. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[31]  L. Jonk,et al.  TAK1 activation of the mouse JunB promoter is mediated through a CCAAT box and NF‐Y , 2001, FEBS letters.

[32]  N. Hunt,et al.  ERK activation and mitogenesis in human airway smooth muscle cells. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[33]  A. Halayko,et al.  Invited Review: Molecular mechanisms of phenotypic plasticity in smooth muscle cells , 2001 .

[34]  A. Halayko,et al.  Molecular mechanisms of phenotypic plasticity in smooth muscle cells. , 2001, Journal of applied physiology.

[35]  T. Lee,et al.  Differential effects of extracellular matrix proteins on human airway smooth muscle cell proliferation and phenotype. , 2000, American journal of respiratory cell and molecular biology.

[36]  Paul A. Overbeek,et al.  TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice , 2000, Nature Medicine.

[37]  T. Muta,et al.  TAK1 mediates an activation signal from toll‐like receptor(s) to nuclear factor‐κB in lipopolysaccharide‐stimulated macrophages , 2000, FEBS letters.

[38]  J. Benovic,et al.  Mechanisms of proliferation synergy by receptor tyrosine kinase and G protein-coupled receptor activation in human airway smooth muscle. , 2000, American journal of respiratory cell and molecular biology.

[39]  B. Foxwell,et al.  Inhibition of endotoxin-induced TNF-alpha production in macrophages by 5Z-7-oxo-zeaenol and other fungal resorcylic acid lactones. , 1999, International journal of immunopharmacology.

[40]  F. Marumo,et al.  TGF-βbgr-activating kinase-1 inhibits cell cycle and expression of cyclin D1 and A in LLC-PK1 cells , 1999 .

[41]  J. Benovic,et al.  MAPK superfamily activation in human airway smooth muscle: mitogenesis requires prolonged p42/p44 activation. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[42]  W. Toriumi,et al.  Functional Interactions of Transforming Growth Factor β-activated Kinase 1 with IκB Kinases to Stimulate NF-κB Activation* , 1999, The Journal of Biological Chemistry.

[43]  S. Sato,et al.  A radicicol-related macrocyclic nonaketide compound, antibiotic LL-Z1640-2, inhibits the JNK/p38 pathways in signal-specific manner. , 1999, Biochemical and biophysical research communications.

[44]  J. Ninomiya-Tsuji,et al.  The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathway , 1999, Nature.

[45]  M. Drumm.  in vivo. , 1999 .

[46]  D. Postma,et al.  Characteristics of airway hyperresponsiveness in asthma and chronic obstructive pulmonary disease. , 1998, American journal of respiratory and critical care medicine.

[47]  Y. Nasuhara,et al.  Expression of epidermal growth factor and epidermal growth factor receptor immunoreactivity in the asthmatic human airway. , 1998, American journal of respiratory and critical care medicine.

[48]  H. Sakurai,et al.  TGF-beta-activated kinase 1 stimulates NF-kappa B activation by an NF-kappa B-inducing kinase-independent mechanism. , 1998, Biochemical and biophysical research communications.

[49]  W. Kuo,et al.  MEK1 is required for PDGF-induced ERK activation and DNA synthesis in tracheal myocytes. , 1997, The American journal of physiology.

[50]  A. Halayko,et al.  Markers of airway smooth muscle cell phenotype. , 1996, The American journal of physiology.

[51]  K. Irie,et al.  Identification of a Member of the MAPKKK Family as a Potential Mediator of TGF-β Signal Transduction , 1995, Science.

[52]  M. Kelleher,et al.  Role of MAP kinase activation in bovine tracheal smooth muscle mitogenesis. , 1995, The American journal of physiology.

[53]  P. Paré,et al.  Platelet-derived growth factor and its receptor in lungs from patients with asthma and chronic airflow obstruction. , 1994, The American journal of physiology.

[54]  A. Stewart,et al.  Inhibition by salbutamol of the proliferation of human airway smooth muscle cells grown in culture , 1994, British journal of pharmacology.

[55]  M. Ebina,et al.  Cellular hypertrophy and hyperplasia of airway smooth muscles underlying bronchial asthma. A 3-D morphometric study. , 1993, The American review of respiratory disease.

[56]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.