Alison Bamberg1,2, Elizabeth F Redente1,3,4, Steve D Groshong5,3, Rubin M Tuder3, Carlyne D Cool3, Rebecca C Keith5,3, Benjamin L Edelman1, Bart P Black1, Gregory P Cosgrove5,3, Murry W Wynes1,3, Douglas Curran-Everett6, Stijn De Langhe7, Luis A Ortiz8, Andrew Thorburn9, David W H Riches1,2,3,9,4. 1. 1 Program in Cell Biology, Department of Pediatrics. 2. 2 Department of Immunology and Microbiology. 3. 3 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, and. 4. 4 Department of Research, Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado. 5. 5 Department of Medicine, and. 6. 6 Division of Biostatistics and Bioinformatics, National Jewish Health, Denver, Colorado. 7. 7 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and. 8. 8 Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania. 9. 9 Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado.
Abstract
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic interstitial lung disease characterized by (myo)fibroblast accumulation and collagen deposition. Resistance to Fas-induced apoptosis is thought to facilitate (myo)fibroblast persistence in fibrotic lung tissues by poorly understood mechanisms. OBJECTIVES: To test the hypothesis that PTPN13 (protein tyrosine phosphatase-N13) is expressed by IPF lung (myo)fibroblasts, promotes their resistance to Fas-induced apoptosis, and contributes to the development of pulmonary fibrosis. METHODS: PTPN13 was localized in lung tissues from patients with IPF and control subjects by immunohistochemical staining. Inhibition of PTPN13 function in primary IPF and normal lung (myo)fibroblasts was accomplished by: 1) downregulation with TNF-α (tumor necrosis factor-α)/IFN-γ, 2) siRNA knockdown, or 3) a cell-permeable Fas/PTPN13 interaction inhibitory peptide. The role of PTPN13 in the development of pulmonary fibrosis was assessed in mice with genetic deficiency of PTP-BL, the murine ortholog of PTPN13. MEASUREMENTS AND MAIN RESULTS: PTPN13 was constitutively expressed by (myo)fibroblasts in the fibroblastic foci of patients with IPF. Human lung (myo)fibroblasts, which are resistant to Fas-induced apoptosis, basally expressed PTPN13 in vitro. TNF-α/IFN-γ or siRNA-mediated PTPN13 downregulation and peptide-mediated inhibition of the Fas/PTPN13 interaction in human lung (myo)fibroblasts promoted Fas-induced apoptosis. Bleomycin-challenged PTP-BL-/- mice, while developing inflammatory lung injury, exhibited reduced pulmonary fibrosis compared with wild-type mice. CONCLUSIONS: These findings suggest that PTPN13 mediates the resistance of human lung (myo)fibroblasts to Fas-induced apoptosis and promotes pulmonary fibrosis in mice. Our results suggest that strategies aimed at interfering with PTPN13 expression or function may represent a novel strategy to reduce fibrosis in IPF.
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic interstitial lung disease characterized by (myo)fibroblast accumulation and collagen deposition. Resistance to Fas-induced apoptosis is thought to facilitate (myo)fibroblast persistence in fibrotic lung tissues by poorly understood mechanisms. OBJECTIVES: To test the hypothesis that PTPN13 (protein tyrosine phosphatase-N13) is expressed by IPF lung (myo)fibroblasts, promotes their resistance to Fas-induced apoptosis, and contributes to the development of pulmonary fibrosis. METHODS:PTPN13 was localized in lung tissues from patients with IPF and control subjects by immunohistochemical staining. Inhibition of PTPN13 function in primary IPF and normal lung (myo)fibroblasts was accomplished by: 1) downregulation with TNF-α (tumor necrosis factor-α)/IFN-γ, 2) siRNA knockdown, or 3) a cell-permeable Fas/PTPN13 interaction inhibitory peptide. The role of PTPN13 in the development of pulmonary fibrosis was assessed in mice with genetic deficiency of PTP-BL, the murine ortholog of PTPN13. MEASUREMENTS AND MAIN RESULTS:PTPN13 was constitutively expressed by (myo)fibroblasts in the fibroblastic foci of patients with IPF. Human lung (myo)fibroblasts, which are resistant to Fas-induced apoptosis, basally expressed PTPN13 in vitro. TNF-α/IFN-γ or siRNA-mediated PTPN13 downregulation and peptide-mediated inhibition of the Fas/PTPN13 interaction in human lung (myo)fibroblasts promoted Fas-induced apoptosis. Bleomycin-challenged PTP-BL-/- mice, while developing inflammatory lung injury, exhibited reduced pulmonary fibrosis compared with wild-type mice. CONCLUSIONS: These findings suggest that PTPN13 mediates the resistance of human lung (myo)fibroblasts to Fas-induced apoptosis and promotes pulmonary fibrosis in mice. Our results suggest that strategies aimed at interfering with PTPN13 expression or function may represent a novel strategy to reduce fibrosis in IPF.
Authors: Seung-Ick Cha; Steve D Groshong; Stephen K Frankel; Ben L Edelman; Gregory P Cosgrove; Jennifer L Terry-Powers; Linda K Remigio; Douglas Curran-Everett; Kevin K Brown; Carlyne D Cool; David W H Riches Journal: Am J Respir Cell Mol Biol Date: 2009-04-16 Impact factor: 6.914
Authors: Jacob M Gump; Leah Staskiewicz; Michael J Morgan; Alison Bamberg; David W H Riches; Andrew Thorburn Journal: Nat Cell Biol Date: 2013-12-08 Impact factor: 28.824
Authors: Konstantin Tsoyi; Xiaoliang Liang; Giulia De Rossi; Stefan W Ryter; Kevin Xiong; Sarah G Chu; Xiaoli Liu; Bonna Ith; Lindsay J Celada; Freddy Romero; Matthew J Robertson; Anthony J Esposito; Sergio Poli; Souheil El-Chemaly; Mark A Perrella; YuanYuan Shi; James Whiteford; Ivan O Rosas Journal: Am J Respir Crit Care Med Date: 2021-08-01 Impact factor: 30.528
Authors: Elizabeth F Redente; Sangeeta Chakraborty; Satria Sajuthi; Bart P Black; Ben L Edelman; Max A Seibold; David Wh Riches Journal: JCI Insight Date: 2020-12-08