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.
Original language | English |
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Pages (from-to) | 470-477 |
Number of pages | 8 |
Journal | Toxicological Sciences |
Volume | 90 |
Issue number | 2 |
DOIs | |
State | Published - Apr 2006 |
Bibliographical note
Funding Information:We thank H. S. Lee for expert assistance of the data analysis. This work was supported by grant No. R04-2002–000–00023–0 from the Basic Research Program of the Korea Science & Engineering Foundation and a Korea Research Foundation Grant (KRF-2001–015-FP0055).
Keywords
- Crystalline silica
- Mitogen activated protein kinases
- NF-κB
- RAW 264.7 macrophages
- Src tyrosine kinases