ToxSci Advance Access originally published online on January 23, 2006
Toxicological Sciences 2006 90(2):470-477; doi:10.1093/toxsci/kfj096
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Src Tyrosine Kinases Mediate Crystalline Silica-Induced NF-
B Activation through Tyrosine Phosphorylation of IB-
and p65 NF-B in RAW 264.7 Macrophages
* Department of Physiology, Pharmacology, and Biochemistry, Division of Cell Biology, Ewha Medical Research Center, Ewha Womans University College of Medicine, Seoul, Korea
Received October 6, 2005; accepted January 3, 2006
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-
B activation and whether NF-B 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-B activation in a dose-dependent manner. Furthermore, these kinase inhibitors suppressed silica-induced tyrosine phosphorylation of IB-
and p65 NF-B. Within a similar time frame, c-Src and Lck were physically associated with IB- and with p65 NF-B. 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-B activation. These results suggest that c-Src and Lck act for silica-induced NF-B activation by mediating the tyrosine phosphorylations of IB- and p65 NF-B. However, the Src TK-dependent activation of ERK1/2 may not be involved in the silica signaling pathway leading to NF-B activation.
Key Words: crystalline silica; Src tyrosine kinases; NF-B; mitogen activated protein kinases; RAW 264.7 macrophages.
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