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Silica induces nuclear factor-κB activation through tyrosine phosphorylation of IκB-α in RAW264.7 macrophages

Title
Silica induces nuclear factor-κB activation through tyrosine phosphorylation of IκB-α in RAW264.7 macrophages
Authors
Kang J.L.Pack I.S.Hong S.M.Lee H.S.Castranova V.
Ewha Authors
이지희
SCOPUS Author ID
이지희scopus
Issue Date
2000
Journal Title
Toxicology and Applied Pharmacology
ISSN
0041-008XJCR Link
Citation
vol. 169, no. 1, pp. 59 - 65
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
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. (C) 2000 Academic Press.
DOI
10.1006/taap.2000.9039
Appears in Collections:
의과대학 > 의학과 > Journal papers
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