Asbestos-induced peribronchiolar cell proliferation and cytokine production are attenuated in lungs of protein kinase C-δ knockout mice

Arti Shukla, Karen M. Lounsbury, Trisha F. Barrett, Joanna Gell, Mercedes Rincon, Kelly J. Butnor, Douglas J. Taatjes, Gerald S. Davis, Pamela Vacek, Keiichi I. Nakayama, Keiko Nakayama, Chad Steele, Brooke T. Mossman

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38 Citations (Scopus)

Abstract

The signaling pathways leading to the development of asbestos-associated diseases are poorly understood. Here we used normal and protein kinase C (PKC)-δ knockout (PKCδ-/-) mice to demonstrate multiple roles of PKC-δ in the development of cell proliferation and inflammation after inhalation of chrysotile asbestos. At 3 days, asbestos-induced peribronchiolar cell proliferation in wild-type mice was attenuated in PKCδ-/- mice. Cytokine profiles in bronchoalveolar lavage fluids showed increases in interleukin (IL)-1β, IL-4, IL-6, and IL-13 that were decreased in PKCδ-/- mice. At 9 days, microarray and quantitative reverse transcriptase-polymerase chain reaction analysis of lung tissues revealed increased mRNA levels of the profibrotic cytokine, IL-4, in asbestos-exposed wildtype mice but not PKCδ-/- mice. PKCδ-/- mice also exhibited decreased lung infiltration of polymorphonuclear cells, natural killer cells, and macrophages in bronchoalveolar lavage fluid and lung, as well as increased numbers of B lymphocytes and plasma cells. These changes were accompanied by elevated mRNA levels of immunoglobulin chains. These data show that modulation of PKC-δ has multiple effects on peribronchiolar cell proliferation, proinflammatory and profibrotic cytokine expression, and immune cell profiles in lung. These results also implicate targeted interruption of PKC-δ as a potential therapeutic option in asbestos-induced lung diseases.

Original languageEnglish
Pages (from-to)140-151
Number of pages12
JournalAmerican Journal of Pathology
Volume170
Issue number1
DOIs
Publication statusPublished - 2007 Jan 1
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Shukla, A., Lounsbury, K. M., Barrett, T. F., Gell, J., Rincon, M., Butnor, K. J., Taatjes, D. J., Davis, G. S., Vacek, P., Nakayama, K. I., Nakayama, K., Steele, C., & Mossman, B. T. (2007). Asbestos-induced peribronchiolar cell proliferation and cytokine production are attenuated in lungs of protein kinase C-δ knockout mice. American Journal of Pathology, 170(1), 140-151. https://doi.org/10.2353/ajpath.2007.060381