title: Amphiregulin, an epidermal growth factor receptor ligand, plays an essential role in the pathogenesis of transforming growth factor-β-induced pulmonary fibrosis.
abstract: Dysregulated amphiregulin (AR) expression and EGR receptor (EGFR) activation have been described in animal models of pulmonary fibrosis and in patients with idiopathic pulmonary fibrosis. However, the exact role of AR in the pathogenesis of pulmonary fibrosis has not been clearly defined. Here, we show that a potent profibrogenic cytokine TGF-β1 significantly induced the expression of AR in lung fibroblasts in vitro and in murine lungs in vivo. AR stimulated NIH3T3 fibroblast cell proliferation in a dose-dependent manner. Silencing of AR expression by siRNA or chemical inhibition of EGFR signaling, utilizing AG1478 and gefitinib, significantly reduced the ability of TGF-β1 to stimulate fibroblast proliferation and expression of α-smooth muscle actin, collagen, and other extracellular matrix-associated genes. TGF-β1-stimulated activation of Akt, ERK, and Smad signaling was also significantly inhibited by these interventions. Consistent with these in vitro findings, AR expression was impressively increased in the lungs of TGF-β1 transgenic mice, and either siRNA silencing of AR or chemical inhibition of EGFR signaling significantly reduced TGF-β1-stimulated collagen accumulation in the lung. These studies showed a novel regulatory role for AR in the pathogenesis of TGF-β1-induced pulmonary fibrosis. In addition, these studies suggest that AR, or AR-activated EGFR signaling, is a potential therapeutic target for idiopathic pulmonary fibrosis associated with TGF-β1 activation.
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8057, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Lee
authors.forename: Won-Kyung
authors.initials: WK
authors.lastname: Cho
authors.forename: Min-Jong
authors.initials: MJ
authors.lastname: Kang
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Koff
authors.forename: Pyeong-Oh
authors.initials: PO
authors.lastname: Yoon
authors.forename: Jeiwook
authors.initials: J
authors.lastname: Chae
authors.forename: Han-Oh
authors.initials: HO
authors.lastname: Park
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
authors.forename: Chun Geun
authors.initials: CG
authors.lastname: Lee
mesh_terms: D066258:Amphiregulin; D000818:Animals; D049109:Cell Proliferation; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008024:Ligands; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases