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KMID : 0811720000040000010
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Korean Journal of Physiology & Pharmacology
2000 Volume.4 No. 0 p.10 ~ p.0
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Silica Induces Nuclear Factor-κB Activation Through Tyrosine Phosphorylation of IκB-α in Macrophages
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Lee Ji-Hee
Pack In-Soon
Hong Su-Min
Lee Hee-Sui
Hah Jong-Sik
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Abstract
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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-κB in macrophages. The question is raised whether PTK stimulation and NF-κB activation in silica-stimulated macrophages are directly connected through tyrosine phosphorylation of IκB-α. Results indicate that stimulation of macrophages with silica led to NF-κB activation through tyrosine phosphorylation without serine phosphorylation. Specific inhibitors of protein tyrosine kinase, such as genistein and tyrophostin AG126, prevented tyrosine phosphorylation of IκB-α in response to silica. IκB-α protein levels remained relatively unchanged for up to 60 min after silica stimulation. Moreover inhibition of proteasome proteolytic activity did not affect NF-κB activation by silica. Antioxidants, such as superoxide dismutase (SOD), N-acetylcysteine (NAC), and pyrrolidine dithiocarbamate (PDTC), blocked tyrosine phosphorylation of IκB-α induced by silica, suggesting reactive oxygen species (ROS) may be important regulatory molecules in NF-κB activation through tyrosine phosphorylation of IκB-α. The results suggest that tyrosine phosphorylation of IκB-α represents a proteasome proteolytic activity-independent mechanism for NF-κB activation that directly couples NF-κB to cellular tyrosine kinase in silica-stimulated macrophages. This proposed mechanism of NF-κB activation induced by silica could be used as a target for development of antiinflammatory and antifibrosis drugs. Toxicol Appl Pharmacol 2000 in press; Supported by The Korea Science and Engineering Foundation through the Center for Cell Signaling Research at Ewha Womans University (1998 G 0102).
Source: Korean Journal of Physiology & Pharmacology.2000 Oct;4(Suppl):S18-S18
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