Role of cathepsin S-dependent epithelial cell apoptosis in IFN-γ-induced alveolar remodeling and pulmonary emphysema

Tao Zheng, Min Jong Kang, Kristina Crothers, Zhou Zhu, Wei Liu, Chun Geun Lee, Lesley A. Rabach, Harold A. Chapman, Robert J. Homer, David Aldous, George DeSanctis, Stephen Underwood, Michael Graupe, Richard A. Flavell, John A. Schmidt, Jack A. Elias

Research output: Contribution to journalArticle

Abstract

Th1/Tc1 inflammation and remodeling responses characterized by tissue atrophy and destruction frequently coexist in human diseases and disorders. However, the mechanisms that are used by Th1/Tc1 cytokines, like IFN-γ, to induce these responses have not been defined. To elucidate the mechanism(s) of IFN-γ-induced tissue remodeling and destruction, we characterized the pathway that lung-targeted, transgenic IFN-γ uses to induce alveolar remodeling in a murine pulmonary emphysema modeling system. In these mice, transgenic IFN-γ caused epithelial cell DNA injury and apoptosis detectable with TUNEL (Roche) and dual annexin V and propidium iodide staining. These responses were associated with death receptor and mitochondrial apoptosis pathway activation. Importantly, apoptosis inhibition with a caspase inhibitor (N-benzylcarboxy-Val-Ala-Asp-fluoromethylketone) or a null mutation of caspase-3 blocked this DNA injury and apoptosis response and significantly ameliorated IFN-γ-induced emphysema. These interventions also ameliorated IFN-γ-induced inflammation and decreased pulmonary protease burden. Selective cathepsin S inhibition and a null mutation of cathepsin S also decreased IFN-γ-induced DNA injury, apoptosis, emphysema, inflammation, and protease accumulation. These studies demonstrate that cathepsin S-dependent epithelial cell apoptosis is a critical event in the pathogenesis of IFN-γ-induced alveolar remodeling and emphysema. They also link inflammation, protease/antiprotease alterations, and protease-dependent apoptosis in the pathogenesis of Th1/Tc1 cytokine-induced tissue remodeling and destructive responses.

Original languageEnglish (US)
Pages (from-to)8106-8115
Number of pages10
JournalJournal of Immunology
Volume174
Issue number12
StatePublished - Jun 15 2005
Externally publishedYes

Fingerprint

cathepsin S
Pulmonary Emphysema
Epithelial Cells
Apoptosis
Emphysema
Peptide Hydrolases
DNA Damage
Inflammation
Cytokines
Death Domain Receptors
Mutation
Caspase Inhibitors
Propidium
Annexin A5
In Situ Nick-End Labeling
Protease Inhibitors
Caspase 3
Transgenic Mice
Atrophy
Pneumonia

ASJC Scopus subject areas

  • Immunology

Cite this

Zheng, T., Kang, M. J., Crothers, K., Zhu, Z., Liu, W., Lee, C. G., ... Elias, J. A. (2005). Role of cathepsin S-dependent epithelial cell apoptosis in IFN-γ-induced alveolar remodeling and pulmonary emphysema. Journal of Immunology, 174(12), 8106-8115.

Role of cathepsin S-dependent epithelial cell apoptosis in IFN-γ-induced alveolar remodeling and pulmonary emphysema. / Zheng, Tao; Kang, Min Jong; Crothers, Kristina; Zhu, Zhou; Liu, Wei; Lee, Chun Geun; Rabach, Lesley A.; Chapman, Harold A.; Homer, Robert J.; Aldous, David; DeSanctis, George; Underwood, Stephen; Graupe, Michael; Flavell, Richard A.; Schmidt, John A.; Elias, Jack A.

In: Journal of Immunology, Vol. 174, No. 12, 15.06.2005, p. 8106-8115.

Research output: Contribution to journalArticle

Zheng, T, Kang, MJ, Crothers, K, Zhu, Z, Liu, W, Lee, CG, Rabach, LA, Chapman, HA, Homer, RJ, Aldous, D, DeSanctis, G, Underwood, S, Graupe, M, Flavell, RA, Schmidt, JA & Elias, JA 2005, 'Role of cathepsin S-dependent epithelial cell apoptosis in IFN-γ-induced alveolar remodeling and pulmonary emphysema', Journal of Immunology, vol. 174, no. 12, pp. 8106-8115.
Zheng T, Kang MJ, Crothers K, Zhu Z, Liu W, Lee CG et al. Role of cathepsin S-dependent epithelial cell apoptosis in IFN-γ-induced alveolar remodeling and pulmonary emphysema. Journal of Immunology. 2005 Jun 15;174(12):8106-8115.
Zheng, Tao ; Kang, Min Jong ; Crothers, Kristina ; Zhu, Zhou ; Liu, Wei ; Lee, Chun Geun ; Rabach, Lesley A. ; Chapman, Harold A. ; Homer, Robert J. ; Aldous, David ; DeSanctis, George ; Underwood, Stephen ; Graupe, Michael ; Flavell, Richard A. ; Schmidt, John A. ; Elias, Jack A. / Role of cathepsin S-dependent epithelial cell apoptosis in IFN-γ-induced alveolar remodeling and pulmonary emphysema. In: Journal of Immunology. 2005 ; Vol. 174, No. 12. pp. 8106-8115.
@article{8802deba102c46fe82f678a63839f1a1,
title = "Role of cathepsin S-dependent epithelial cell apoptosis in IFN-γ-induced alveolar remodeling and pulmonary emphysema",
abstract = "Th1/Tc1 inflammation and remodeling responses characterized by tissue atrophy and destruction frequently coexist in human diseases and disorders. However, the mechanisms that are used by Th1/Tc1 cytokines, like IFN-γ, to induce these responses have not been defined. To elucidate the mechanism(s) of IFN-γ-induced tissue remodeling and destruction, we characterized the pathway that lung-targeted, transgenic IFN-γ uses to induce alveolar remodeling in a murine pulmonary emphysema modeling system. In these mice, transgenic IFN-γ caused epithelial cell DNA injury and apoptosis detectable with TUNEL (Roche) and dual annexin V and propidium iodide staining. These responses were associated with death receptor and mitochondrial apoptosis pathway activation. Importantly, apoptosis inhibition with a caspase inhibitor (N-benzylcarboxy-Val-Ala-Asp-fluoromethylketone) or a null mutation of caspase-3 blocked this DNA injury and apoptosis response and significantly ameliorated IFN-γ-induced emphysema. These interventions also ameliorated IFN-γ-induced inflammation and decreased pulmonary protease burden. Selective cathepsin S inhibition and a null mutation of cathepsin S also decreased IFN-γ-induced DNA injury, apoptosis, emphysema, inflammation, and protease accumulation. These studies demonstrate that cathepsin S-dependent epithelial cell apoptosis is a critical event in the pathogenesis of IFN-γ-induced alveolar remodeling and emphysema. They also link inflammation, protease/antiprotease alterations, and protease-dependent apoptosis in the pathogenesis of Th1/Tc1 cytokine-induced tissue remodeling and destructive responses.",
author = "Tao Zheng and Kang, {Min Jong} and Kristina Crothers and Zhou Zhu and Wei Liu and Lee, {Chun Geun} and Rabach, {Lesley A.} and Chapman, {Harold A.} and Homer, {Robert J.} and David Aldous and George DeSanctis and Stephen Underwood and Michael Graupe and Flavell, {Richard A.} and Schmidt, {John A.} and Elias, {Jack A.}",
year = "2005",
month = "6",
day = "15",
language = "English (US)",
volume = "174",
pages = "8106--8115",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "12",

}

TY - JOUR

T1 - Role of cathepsin S-dependent epithelial cell apoptosis in IFN-γ-induced alveolar remodeling and pulmonary emphysema

AU - Zheng, Tao

AU - Kang, Min Jong

AU - Crothers, Kristina

AU - Zhu, Zhou

AU - Liu, Wei

AU - Lee, Chun Geun

AU - Rabach, Lesley A.

AU - Chapman, Harold A.

AU - Homer, Robert J.

AU - Aldous, David

AU - DeSanctis, George

AU - Underwood, Stephen

AU - Graupe, Michael

AU - Flavell, Richard A.

AU - Schmidt, John A.

AU - Elias, Jack A.

PY - 2005/6/15

Y1 - 2005/6/15

N2 - Th1/Tc1 inflammation and remodeling responses characterized by tissue atrophy and destruction frequently coexist in human diseases and disorders. However, the mechanisms that are used by Th1/Tc1 cytokines, like IFN-γ, to induce these responses have not been defined. To elucidate the mechanism(s) of IFN-γ-induced tissue remodeling and destruction, we characterized the pathway that lung-targeted, transgenic IFN-γ uses to induce alveolar remodeling in a murine pulmonary emphysema modeling system. In these mice, transgenic IFN-γ caused epithelial cell DNA injury and apoptosis detectable with TUNEL (Roche) and dual annexin V and propidium iodide staining. These responses were associated with death receptor and mitochondrial apoptosis pathway activation. Importantly, apoptosis inhibition with a caspase inhibitor (N-benzylcarboxy-Val-Ala-Asp-fluoromethylketone) or a null mutation of caspase-3 blocked this DNA injury and apoptosis response and significantly ameliorated IFN-γ-induced emphysema. These interventions also ameliorated IFN-γ-induced inflammation and decreased pulmonary protease burden. Selective cathepsin S inhibition and a null mutation of cathepsin S also decreased IFN-γ-induced DNA injury, apoptosis, emphysema, inflammation, and protease accumulation. These studies demonstrate that cathepsin S-dependent epithelial cell apoptosis is a critical event in the pathogenesis of IFN-γ-induced alveolar remodeling and emphysema. They also link inflammation, protease/antiprotease alterations, and protease-dependent apoptosis in the pathogenesis of Th1/Tc1 cytokine-induced tissue remodeling and destructive responses.

AB - Th1/Tc1 inflammation and remodeling responses characterized by tissue atrophy and destruction frequently coexist in human diseases and disorders. However, the mechanisms that are used by Th1/Tc1 cytokines, like IFN-γ, to induce these responses have not been defined. To elucidate the mechanism(s) of IFN-γ-induced tissue remodeling and destruction, we characterized the pathway that lung-targeted, transgenic IFN-γ uses to induce alveolar remodeling in a murine pulmonary emphysema modeling system. In these mice, transgenic IFN-γ caused epithelial cell DNA injury and apoptosis detectable with TUNEL (Roche) and dual annexin V and propidium iodide staining. These responses were associated with death receptor and mitochondrial apoptosis pathway activation. Importantly, apoptosis inhibition with a caspase inhibitor (N-benzylcarboxy-Val-Ala-Asp-fluoromethylketone) or a null mutation of caspase-3 blocked this DNA injury and apoptosis response and significantly ameliorated IFN-γ-induced emphysema. These interventions also ameliorated IFN-γ-induced inflammation and decreased pulmonary protease burden. Selective cathepsin S inhibition and a null mutation of cathepsin S also decreased IFN-γ-induced DNA injury, apoptosis, emphysema, inflammation, and protease accumulation. These studies demonstrate that cathepsin S-dependent epithelial cell apoptosis is a critical event in the pathogenesis of IFN-γ-induced alveolar remodeling and emphysema. They also link inflammation, protease/antiprotease alterations, and protease-dependent apoptosis in the pathogenesis of Th1/Tc1 cytokine-induced tissue remodeling and destructive responses.

UR - http://www.scopus.com/inward/record.url?scp=20444368841&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20444368841&partnerID=8YFLogxK

M3 - Article

C2 - 15944319

AN - SCOPUS:20444368841

VL - 174

SP - 8106

EP - 8115

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 12

ER -