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
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
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DOI：
10.1093/toxsci/kfj096
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发表时间：
2006-04-01
影响因子：
3.8
通讯作者：
Kim, HR
中科院分区：
文献类型：
--
作者：
Kang, JL;Jung, HJ;Kim, HR
蛋白酪氨酸激酶（PTKs）和丝裂原活化蛋白激酶（MAPKs）已被证明在二氧化硅诱导的信号通路中起关键作用。在本研究中，我们研究了Src家族TKs是否在结晶二氧化硅诱导的NF-kappa B激活中发挥作用，以及在小鼠腹膜巨噬细胞系RAW 264.7细胞中，NF-kappa B激活是否需要Src tk依赖性MAPK活性。选择性Src TK抑制剂，damnacanthal或PP1，以剂量依赖的方式抑制二氧化硅诱导的NF-kappa B活化。此外，这些激酶抑制剂抑制了二氧化硅诱导的I kappa b - α和p65 NF-kappa b的酪氨酸磷酸化，在相似的时间框架内，c-Src和Lck与I kappa b - α和p65 NF-kappa b有物理关联。二氧化硅刺激细胞外信号调节激酶1和2 （ERK1/2）的磷酸化，但不刺激p38 MAPK和c-Jun nh2末端激酶1和2 （JNK1/2）的磷酸化。Damnacanthal或PP1实质上阻断了二氧化硅诱导的ERK1/2的激活。此外，ERK1/2抑制剂PD98059或p38 MAPK抑制剂SB203580无法抑制二氧化硅诱导的NF-kappa B活化。这些结果表明，c-Src和Lck通过介导I kappa B- α和p65 NF-kappa B的酪氨酸磷酸化作用于二氧化硅诱导的NF-kappa B激活。然而，Src tk依赖性的ERK1/2激活可能不参与导致NF-kappa B激活的二氧化硅信号通路。
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-kappa B activation and whether NF-kappa 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-kappa B activation in a dose-dependent manner. Furthermore, these kinase inhibitors suppressed silica-induced tyrosine phosphorylation of I kappa B-alpha and p65 NF-kappa B. Within a similar time frame, c-Src and Lck were physically associated with I kappa B-alpha and with p65 NF-kappa 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-kappa B activation. These results suggest that c-Src and Lck act for silica-induced NF-kappa B activation by mediating the tyrosine phosphorylations of I kappa B-alpha and p65 NF-kappa B. However, the Src TK-dependent activation of ERK1/2 may not be involved in the silica signaling pathway leading to NF-kappa B activation.