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Silica induces nuclear factor-B activation through tyrosine phosphorylation of 1kB-x in RAW264.7 macrophages.
Kang JL; Pack IS; Hong SM; Lee HS; Castranova V
Toxicol Appl Pharmacol 2000 Nov; 169(1):59-65
It was previously reported that protein tyrosine kinase (PTK) but not protein kinase C or A plays an important role in silica-induced activation of NF-kB in macrophages. The question is raised whether PTK stimulation and NF-kB activation in silica-stimulated macrophages are directly connected through tyrosine phosphorylation of IkB-a. Results indicate that stimulation of macrophages with silica led to NF-kB activation through tyrosine phosphorylation without serine phosphorylation. Specific inhibitors of protein tyrosine kinase, such as genistein and tyrophostin AG126, prevented tyrosine phosphorylation of IkB-a in response to silica. IkB-a protein levels remained relatively unchanged for up to 60 min after silica stimulation. Moreover, inhibition of proteasome proteolytic activity did not affect NF-kB activation by silica. Antioxidants, such as superoxide dismutase (SOD), N-acetylcysteine (NAC), and pyrrolidine dithiocarbamate (PDTC), blocked tyrosine phosphorylation of IkB-a induced by silica, suggesting reactive oxygen species (ROS) may be important regulatory molecules in NF-kB activation through tyrosine phosphorylation of IkB-a. The results suggest that tyrosine phosphorylation of IkB-a represents a proteasome proteolytic activity-independent mechanism for NF-kB activation that directly couples NF-kB to cellular tyrosine kinase in silica-stimulated macrophages. This proposed mechanism of NF-kB activation induced by silica could be used as a target for development of antiinflammatory and antifibrosis drugs.
Silica-dusts; Silicates; Antioxidants; Lung-disorders; Pulmonary-system-disorders; Respiratory-system-disorders; Lung-fibrosis; Silicosis; Author Keywords: silica; NF-kB; tyrosine phosphorylation; IkB-a; macrophages; reactive oxygen species
Issue of Publication
Toxicology and Applied Pharmacology
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