TY - JOUR
T1 - Protein tyrosine phosphatase-N13 promotes myofibroblast resistance to apoptosis in idiopathic pulmonary fibrosis
AU - Bamberg, Alison
AU - Redente, Elizabeth F.
AU - Groshong, Steve D.
AU - Tuder, Rubin M.
AU - Cool, Carlyne D.
AU - Keith, Rebecca C.
AU - Edelman, Benjamin L.
AU - Black, Bart P.
AU - Cosgrove, Gregory P.
AU - Wynes, Murry W.
AU - Curran-Everett, Douglas
AU - De Langhe, Stijn
AU - Ortiz, Luis A.
AU - Thorburn, Andrew
AU - Riches, David W.H.
N1 - Publisher Copyright:
© 2018 by the American Thoracic Society.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - 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-a)/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 inmice 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 peptidemediated inhibition of the Fas/PTPN13 interaction in human lung (myo)fibroblasts promoted Fas-induced apoptosis. Bleomycinchallenged 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.
AB - 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-a)/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 inmice 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 peptidemediated inhibition of the Fas/PTPN13 interaction in human lung (myo)fibroblasts promoted Fas-induced apoptosis. Bleomycinchallenged 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.
KW - (myo)fibroblasts
KW - Apoptosis resistance
KW - PTPN13
KW - Pulmonary fibrosis
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U2 - 10.1164/rccm.201707-1497OC
DO - 10.1164/rccm.201707-1497OC
M3 - Article
C2 - 29727583
AN - SCOPUS:85053426995
SN - 1073-449X
VL - 198
SP - 914
EP - 927
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 7
ER -