Protein Tyrosine Phosphatase-N13 Promotes Myofibroblast Resistance to Apoptosis in Idiopathic Pulmonary Fibrosis.

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.

• Authors: Alison Bamberg, Elizabeth F Redente, Steve D Groshong, Rubin M Tuder, Carlyne D Cool, Rebecca C Keith, Benjamin L Edelman, Bart P Black, Gregory P Cosgrove, Murry W Wynes, Douglas Curran-Everett, Stijn De Langhe, Luis A Ortiz, Andrew Thorburn, David W H Riches
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 198 Issue 7 Pg. 914-927 (10 01 2018) ISSN: 1535-4970 [Electronic] United States
• PMID: 29727583 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• RNA, Small Interfering
• fas Receptor
• Bleomycin
• PTPN13 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 13

Topics

• Animals
• Apoptosis (genetics)
• Biopsy, Needle
• Bleomycin (pharmacology)
• Case-Control Studies
• Down-Regulation
• Drug Resistance, Microbial
• Female
• Humans
• Idiopathic Pulmonary Fibrosis (drug therapy, genetics, pathology)
• Immunohistochemistry
• Male
• Mice
• Mice, Knockout
• Myofibroblasts (metabolism)
• Protein Tyrosine Phosphatase, Non-Receptor Type 13 (genetics)
• RNA, Small Interfering (genetics)
• Reference Values
• Tissue Culture Techniques
• fas Receptor (drug effects)