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
DOIs
StatePublished - Jun 15 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Zheng, T., Kang, M. J., Crothers, K., Zhu, Z., Liu, W., Lee, C. G., Rabach, L. A., Chapman, H. A., Homer, R. J., Aldous, D., DeSanctis, G., Underwood, S., Graupe, M., Flavell, R. A., Schmidt, J. A., & 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. https://doi.org/10.4049/jimmunol.174.12.8106