title: TGF-beta 1 as an enhancer of Fas-mediated apoptosis of lung epithelial cells.
abstract: Transforming growth factor-beta 1 (TGF-beta 1) has important roles in lung fibrosis and the potential to induce apoptosis in several types of cells. We previously demonstrated that apoptosis of lung epithelial cells induced by Fas ligation may be involved in the development of pulmonary fibrosis. In this study, we show that TGF-beta1 induces apoptosis of primary cultured bronchiolar epithelial cells via caspase-3 activation and down-regulation of cyclin-dependent kinase inhibitor p21. Concentrations of TGF-beta 1 that were not sufficient to induce apoptosis alone could enhance agonistic anti-Fas Ab or rFas ligand-mediated apoptosis of cultured bronchiolar epithelial cells. Soluble Fas ligand in the bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF) also induced apoptosis of cultured bronchiolar epithelial cells that was significantly attenuated by anti-TGF-beta Ab. Otherwise, BALF from patients with hypersensitivity pneumonitis (HP) could not induce apoptosis on bronchiolar epithelial cells, despite its comparable amounts of soluble Fas ligand. The concentrations of TGF-beta 1 in BALF from patients with IPF were significantly higher compared with those in BALF from patients with HP or controls. Furthermore, coincubation with the low concentration of TGF-beta 1 and HP BALF created proapoptotic effects comparable with the IPF BALF. In vivo, the administration of TGF-beta 1 could enhance Fas-mediated epithelial cell apoptosis and lung injury via caspase-3 activation in mice. Our results demonstrate a novel role of TGF-beta 1 in the pathophysiology of pulmonary fibrosis as an enhancer of Fas-mediated apoptosis of lung epithelial cells.
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. hagi@kokyu.med.kyushu-u.ac.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Hagimoto
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kuwano
authors.forename: Ichiro
authors.initials: I
authors.lastname: Inoshima
authors.forename: Michihiro
authors.initials: M
authors.lastname: Yoshimi
authors.forename: Norio
authors.initials: N
authors.lastname: Nakamura
authors.forename: Masaki
authors.initials: M
authors.lastname: Fujita
authors.forename: Takashige
authors.initials: T
authors.lastname: Maeyama
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Hara
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D001980:Bronchi / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D015536:Down-Regulation / Q000276:immunology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D053222:Fas Ligand Protein; D006801:Humans; D007275:Injections, Intravenous; D008168:Lung / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D011994:Recombinant Proteins / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D019014:fas Receptor / Q000502:physiology*
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; C493956:CDKN1A protein, human; D061945:Caspase Inhibitors; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019014:fas Receptor; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases