Hernandez-Hansen Valerie, Bard Julie D J, Tarleton Christy A, Wilder Julie A, Lowell Clifford A, Wilson Bridget S, Oliver Janet M
Department of Pathology and Cancer Research and Treatment Center, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
J Immunol. 2005 Dec 15;175(12):7880-8. doi: 10.4049/jimmunol.175.12.7880.
Cross-linking the high-affinity IgE receptor, FcepsilonRI, on mast cells activates signaling pathways leading to the release of preformed inflammatory mediators and the production of cytokines and chemokines associated with allergic disorders. Bone marrow-derived mast cells (BMMCs) from Lyn-deficient (Lyn-/-) mice are hyperresponsive to FcepsilonRI cross-linking with multivalent Ag. Previous studies linked the hyperresponsive phenotype in part to increased Fyn kinase activity and reduced SHIP phosphatase activity in the Lyn-/- BMMCs in comparison with wild-type (WT) cells. In this study, we compared gene expression profiles between resting and Ag-activated WT and Lyn-/- BMMCs to identify other factors that may contribute to the hyperresponsiveness of the Lyn-/- cells. Among genes implicated in the positive regulation of FcepsilonRI signaling, mRNA for the tyrosine kinase, Fyn, and for several proteins contributing to calcium regulation are more up-regulated following Ag stimulation in Lyn-/- BMMCs than in WT BMMCs. Conversely, mRNA for the low-affinity IgG receptor (FcgammaRIIB), implicated in negative regulation of FcepsilonRI-mediated signaling, is more down-regulated in Ag-stimulated Lyn-/- BMMCs than in WT BMMCs. Genes coding for proinflammatory cytokines and chemokines (IL-4, IL-6, IL-13, CSF, CCL1, CCL3, CCL5, CCL7, CCL9, and MIP1beta) are all more highly expressed in Ag-stimulated Lyn-/- mast cells than in WT cells. These microarray data identify Lyn as a negative regulator in Ag-stimulated BMMCs of the expression of genes linked to FcepsilonRI signaling and also to the response pathways that lead to allergy and asthma.
交联肥大细胞上的高亲和力IgE受体FcepsilonRI可激活信号通路，导致预先形成的炎症介质释放，并产生与过敏性疾病相关的细胞因子和趋化因子。来自Lyn缺陷（Lyn-/-）小鼠的骨髓源性肥大细胞（BMMC）对FcepsilonRI与多价抗原的交联反应过度。先前的研究将这种反应过度的表型部分归因于与野生型（WT）细胞相比，Lyn-/- BMMC中Fyn激酶活性增加和SHIP磷酸酶活性降低。在本研究中，我们比较了静止和抗原激活的WT和Lyn-/- BMMC之间的基因表达谱，以确定可能导致Lyn-/-细胞反应过度的其他因素。在与FcepsilonRI信号正调控相关的基因中，酪氨酸激酶Fyn以及几种参与钙调节的蛋白质的mRNA在Lyn-/- BMMC中受到抗原刺激后的上调程度高于WT BMMC。相反，与FcepsilonRI介导的信号负调控相关的低亲和力IgG受体（FcgammaRIIB）的mRNA在抗原刺激的Lyn-/- BMMC中的下调程度高于WT BMMC。编码促炎细胞因子和趋化因子（IL-4、IL-6、IL-13、CSF、CCL1、CCL3、CCL5、CCL7、CCL9和MIP1beta）的基因在抗原刺激的Lyn-/-肥大细胞中的表达均高于WT细胞。这些微阵列数据表明，Lyn是抗原刺激的BMMC中与FcepsilonRI信号相关基因表达以及导致过敏和哮喘的反应途径的负调节因子。
