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 - Funding Information:
Supported by VA Merit Award BX003471 (D.W.H.R.), VA Career Development Award BX002401 (E.F.R.), and Public Health Service grants HL114754 (D.W.H.R.) and HL126732 (S.D.L. and D.W.H.R., Multiple Principal Investigators) from the NHLBI of the NIH.
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 -