Yousefi S, Hoessli D C, Blaser K, Mills G B, Simon H U
Swiss Institute of Allergy and Asthma Research, University of Zurich, Switzerland.
J Exp Med. 1996 Apr 1;183(4):1407-14. doi: 10.1084/jem.183.4.1407.
In allergic diseases, the cytokines interleukin (IL)5 and granulocyte/macrophage colony-stimulating factor (GM-CSF) are upregulated and have been proposed to cause blood and tissue eosinophilia by inhibition of eosinophil apoptosis. We demonstrate herein, in freshly isolated human eosinophils, that the IL-3/IL-5/GM-CSF receptor beta subunit interacts with cytoplasmic tyrosine kinases to induce phosphorylation of several cellular substrates, including the beta subunit itself. The Lyn and Syk intracellular tyrosine kinases constitutively associate at a low level with the IL-3/IL-5/GM-CSF receptor beta subunit in human eosinophils. Stimulation with GM-CSF or IL-5 results in a rapid and transient increase in the amount of Lyn and Syk associated with the IL-3/IL-5/GM-CSF receptor beta subunit. Lyn is required for optimal tyrosine phosphorylation and activation of Syk. In contrast, Syk is not required for optimal tyrosine phosphorylation and activation of Lyn. These data suggest that Lyn is proximal to Syk in a tyrosine kinase cascade that transduces IL-3, IL-5, or GM-CSF signals. Compatible with this model, both Lyn and Syk are essential for the activation of the antiapoptotic pathway(s) induced through the IL-3/IL-5/GM-CSF receptor beta subunit in human eosinophils.
在过敏性疾病中，细胞因子白细胞介素（IL）-5和粒细胞/巨噬细胞集落刺激因子（GM-CSF）上调，并被认为通过抑制嗜酸性粒细胞凋亡导致血液和组织嗜酸性粒细胞增多。我们在此证明，在新鲜分离的人嗜酸性粒细胞中，IL-3/IL-5/GM-CSF受体β亚基与细胞质酪氨酸激酶相互作用，诱导包括β亚基自身在内的几种细胞底物磷酸化。Lyn和Syk细胞内酪氨酸激酶在人嗜酸性粒细胞中以低水平持续与IL-3/IL-5/GM-CSF受体β亚基结合。用GM-CSF或IL-5刺激导致与IL-3/IL-5/GM-CSF受体β亚基结合的Lyn和Syk量迅速且短暂增加。Lyn是Syk最佳酪氨酸磷酸化和激活所必需的。相反，Syk不是Lyn最佳酪氨酸磷酸化和激活所必需的。这些数据表明，在转导IL-3、IL-5或GM-CSF信号的酪氨酸激酶级联反应中，Lyn位于Syk的近端。与此模型一致，Lyn和Syk对于通过人嗜酸性粒细胞中IL-3/IL-5/GM-CSF受体β亚基诱导的抗凋亡途径的激活都是必不可少的。
