Dysregulation of Src family kinases in mast cells from epilepsy-resistant ASK versus epilepsy-prone EL mice
Dysregulation of Src family kinases in mast cells from epilepsy-resistant ASK versus epilepsy-prone EL mice
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DOI：
10.4049/jimmunol.178.1.455
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发表时间：
2007-01-01
影响因子：
4.4
通讯作者：
Kawakami, Toshiaki
中科院分区：
文献类型：
--
作者：
Kitaura, Jiro;Kawakami, Yuko;Kawakami, Toshiaki
EL鼠被用作癫痫模型，而ASK鼠是一种起源于EL鼠群体的抗癫痫变异。在ASK小鼠中，用IgE和Ag刺激很容易诱发肥大细胞依赖性过敏反应，而EL小鼠对这种刺激具有抵抗力。在这项研究中，我们对来自这两个菌株的肥大细胞进行了鉴定。在IL-3和干细胞因子的作用下，ASK肥大细胞的增殖比EL细胞更旺盛。尽管在IgE和Ag刺激下，ASK肥大细胞脱颗粒不如EL肥大细胞强烈，但ASK细胞产生和分泌的肿瘤坏死因子-α和IL-2是EL细胞的数倍。与这些ASK和EL肥大细胞反应分别与Lyn(-/-)和野生型肥大细胞表型相似，ASK细胞中Lyn活性降低。除LYN活性受损外，ASK细胞和LYN(-/-)细胞一样，表现出Syk活性降低，ERK和JNK激活时间延长，Akt活性增强。此外，与LYN相关的脂筏驻留的跨膜适配器蛋白CBP/PAG在ASK细胞中被低磷酸化。重要的是，与LYN(-/-)细胞类似，Fyn在ASK细胞中被过度激活。因此，这些结果与依赖Lyn的CBP/PAG磷酸化负调控Src家族激酶的观点是一致的。这项研究还表明，肥大细胞激活的负性调节因子Lyn的活性降低是ASK小鼠对过敏反应易感性的基础，并暗示Lyn和其他Src家族激酶的失调参与了癫痫的发生。
EL mice have been used as a model of epilepsy, whereas ASK mice are an epilepsy-resistant variant originating from a colony of EL mice. Mast cell-dependent anaphylaxis is easily inducible by stimulation with IgE and Ag in ASK mice, whereas EL mice are resistant to such stimuli. In this study we have characterized mast cells derived from these two strains. ASK mast cells proliferated more vigorously than EL cells in response to IL-3 and stem cell factor. Although ASK mast cells degranulated less vigorously than EL mast cells upon stimulation with IgE and Ag, ASK cells produced and secreted several-fold more TNF-alpha and IL-2 than EL cells. Consistent with the similarities of these ASK and EL mast cell responses with phenotypes of lyn(-/-) and wild-type mast cells, respectively, Lyn activity was reduced in ASK cells. In addition to the impaired Lyn activity, ASK cells just like lyn(-/-) cells exhibited reduced Syk activity, prolonged activation of ERK and JNK, and enhanced activation of Akt. Furthermore, the lipid raft-resident transmembrane adaptor protein Cbp/PAG that associates with Lyn was hypophosphorylated in ASK cells. Importantly, similar to lyn(-/-) cells, Fyn was hyperactivated in ASK cells. Therefore, these results are consistent with the notion that Lyn-dependent phosphorylation of Cbp/PAG negatively regulates Src family kinases. This study also suggests that reduced activity of Lyn, a negative regulator of mast cell activation, underlies the susceptibility of ASK mice to anaphylaxis and implies that dysregulation of Lyn and other Src family kinases contributes to epileptogenesis.