Asbestos-induced peribronchiolar cell proliferation and cytokine production are attenuated in lungs of protein kinase C-delta knockout mice.
The signaling pathways leading to the development of asbestos-associated diseases are poorly understood. Here we used normal and protein kinase C (PKC)-delta knockout (PKCdelta-/-) mice to demonstrate multiple roles of PKC-delta 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 PKCdelta-/- mice. Cytokine profiles in bronchoalveolar lavage fluids showed increases in interleukin (IL)-1beta, IL-4, IL-6, and IL-13 that were decreased in PKCdelta-/- 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 wild-type mice but not PKCdelta-/- mice. PKCdelta-/- 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-delta 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-delta as a potential therapeutic option in asbestos-induced lung diseases.
Shukla
Arti
A
Department of Pathology, University of Vermont, 89 Beaumont Ave., Burlington, VT 05405, USA.
Lounsbury
Karen M
KM
Barrett
Trisha F
TF
Gell
Joanna
J
Rincon
Mercedes
M
Butnor
Kelly J
KJ
Taatjes
Douglas J
DJ
Davis
Gerald S
GS
Vacek
Pamela
P
Nakayama
Keiichi I
KI
Nakayama
Keiko
K
Steele
Chad
C
Mossman
Brooke T
BT
D000818:Animals; D017632:Asbestos, Serpentine / Q000009:adverse effects*; D049109:Cell Proliferation; D015971:Gene Expression Regulation, Enzymologic; D007249:Inflammation; D007378:Interleukins / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008171:Lung Diseases / Q000201:enzymology / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D016131:Lymphocyte Subsets / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics*; D011658:Pulmonary Fibrosis / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D017632:Asbestos, Serpentine; D007378:Interleukins; D051745:Protein Kinase C-delta; D017493:Leukocyte Common Antigens