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Src tyrosine kinases mediate crystalline silica-induced NF-κB activation through tyrosine phosphorylation of IκB-α and p65 NF-κB in rAW 264.7 macrophages

Title
Src tyrosine kinases mediate crystalline silica-induced NF-κB activation through tyrosine phosphorylation of IκB-α and p65 NF-κB in rAW 264.7 macrophages
Authors
Kang J.L.Jung H.J.Lee K.Kim H.R.
Ewha Authors
이지희김형래이경은
SCOPUS Author ID
이지희scopus; 김형래scopus; 이경은scopus
Issue Date
2006
Journal Title
Toxicological Sciences
ISSN
1096-6080JCR Link
Citation
Toxicological Sciences vol. 90, no. 2, pp. 470 - 477
Indexed
SCI; SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
Protein tyrosine kinases (PTKs) and mitogen-activated protein kinases (MAPKs) have been demonstrated to play a crucial role in the signaling pathways induced by silica. In the present study, we investigated whether Src family TKs play a role in crystalline silica-induced NF-κB activation and whether NF-κB activation requires Src TK-dependent MAPK activity in RAW 264.7 cells, a mouse peritoneal macrophage cell line. Selective Src TK inhibitors, damnacanthal or PP1, inhibited silica-induced NF-κB activation in a dose-dependent manner. Furthermore, these kinase inhibitors suppressed silica-induced tyrosine phosphorylation of IκB-α and p65 NF-κB. Within a similar time frame, c-Src and Lck were physically associated with IκB-α and with p65 NF-κB. Silica stimulated the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), but not p38 MAPK and c-Jun NH2-terminal kinase 1 and 2 (JNK1/2). Damnacanthal or PP1 substantially blocked the silica-induced activation of ERK1/2. Moreover, PD98059, an inhibitor of ERK1/2, or SB203580, an inhibitor of p38 MAPK, failed to inhibit silica-induced NF-κB activation. These results suggest that c-Src and Lck act for silica-induced NF-κB activation by mediating the tyrosine phosphorylations of IκB-α and p65 NF-κB. However, the Src TK-dependent activation of ERK1/2 may not be involved in the silica signaling pathway leading to NF-κB activation. © 2006 Oxford University Press.
DOI
10.1093/toxsci/kfj096
Appears in Collections:
의과대학 > 의학과 > Journal papers
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