Crucial role of interleukin-1beta and nitric oxide synthase in silica-induced inflammation and apoptosis in mice.
Crystalline silica stimulates macrophages in vitro to release interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and nitric oxide (NO) and induces apoptosis of macrophages. Because the fibrogenic potential of a particulate paralleled its ability to induce apoptosis in macrophages, we investigated the underlying mechanisms by which IL-1beta and NO mediate apoptosis and inflammation in murine silicosis. First, we demonstrated that silica induced NO production and apoptosis in vitro using the IC-21 macrophage cell line. Both NO release and apoptosis could be inhibited by neutralizing anti-IL-1beta antibody or the NO synthase (NOS) inhibitor N(G)-nitro-L-arginine-methyl ester (L-NAME), demonstrating the requirement for IL-1beta-mediated NO release in silica-induced apoptosis. We exposed IL-1beta knockout (IL-1beta(-/-)) mice, inducible NOS knockout (iNOS(-/-)) mice, and wild-type mice to 250 mg/m(3) silica for 5 h/d for 10 d using an inhalation chamber. Exposure of wild-type mice to silica resulted in lung inflammation, apoptosis, and significantly larger and more numerous silicotic lesions than in IL-1beta(-/-) mice over a 12-wk course. We also exposed iNOS(-/-) mice via inhalation in the same protocol and compared with wild-type mice and demonstrated that iNOS(-/-) mice had significantly reduced apoptosis and inflammation. These results demonstrated an association between apoptosis and inflammation in murine silicosis and support a potential role for IL-1beta-dependent NO-mediated apoptosis in the evolution of silicosis.
Srivastava
Kamal D
KD
Division of Pulmonary and Critical Care Medicine, Department of Environmental Medicine, New York University School of Medicine, New York, USA.
Rom
William N
WN
Jagirdar
Jaishree
J
Yie
Ting-An
TA
Gordon
Terry
T
Tchou-Wong
Kam-Meng
KM
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002460:Cell Line; D004195:Disease Models, Animal; D066298:In Vitro Techniques; D007249:Inflammation / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D012829:Silicosis / Q000276:immunology* / Q000473:pathology
D007375:Interleukin-1; D019001:Nitric Oxide Synthase