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.

Citations per Year

542 Citations

Semantic Scholar estimates that this publication has 542 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Srivastava2002CrucialRO, title={Crucial role of interleukin-1beta and nitric oxide synthase in silica-induced inflammation and apoptosis in mice.}, author={Kamal D. Srivastava and William Rom and Jaishree S. Jagirdar and Ting-an Yie and Terry Gordon and Kam-Meng Tchou-Wong}, journal={American journal of respiratory and critical care medicine}, year={2002}, volume={165 4}, pages={527-33} }