Genetic ablation of the src kinase p59fynT exacerbates pulmonary inflammation in an allergic mouse model
Genetic ablation of the src kinase p59fynT exacerbates pulmonary inflammation in an allergic mouse model
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DOI：
10.1165/ajrcmb.24.4.4266
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发表时间：
2001-04-01
影响因子：
6.4
通讯作者：
Changelian, PS
中科院分区：
文献类型：
--
作者：
Kudlacz, EM;Andresen, CJ;Changelian, PS
p59fynT是src家族中的一种蛋白酪氨酸激酶，与包括t细胞受体在内的许多受体的信号传导有关，并被认为在其中起作用。在p59fynT基因被基因切除的小鼠中，研究了该激酶在抗原驱动的肺部炎症中的作用。与野生型小鼠相比，卵清蛋白致敏的FynKO小鼠对抗原气溶胶暴露的支气管肺泡灌洗液中嗜酸性粒细胞和细胞因子（包括白细胞介素(IL)-4和IL-5）显着增加。与野生型小鼠相比，fynKO小鼠培养的脾细胞中卵白蛋白刺激的IL-5产生也增加，而干扰素γ水平不变。在致敏/生理盐水挑战动物中观察到，从fynKO脾细胞中产生的康纳蛋白a刺激的IL-4水平降低与血清免疫球蛋白（Ig）E水平降低一致，这可能反映了自然杀伤1.1(+)T细胞发育缺陷。与野生型小鼠相比，致敏fynKO小鼠的IgE水平在重复抗原刺激后出现了正常化，这表明IL-4是次要来源。总的来说，这些数据表明fyn是小鼠过敏性气道炎症的负调节因子，因为它的缺失促进了向T- helper-2表型的转变，这可能反映了该激酶在T细胞受体信号传导中的作用。
p59fynT is a protein tyrosine kinase in the src family that has been associated with and believed to function in the signaling of many receptors, including the T-cell receptor. A role for the kinase in antigen-driven pulmonary inflammation was examined using mice whose p59fynT gene had been genetically ablated. FynKO mice that were sensitized to ovalbumin exhibited a marked increase in bronchoalveolar lavage eosinophils and cytokines, including interleukin (IL)-4 and IL-5, relative to wild-type mice in response to antigen aerosol exposure. Ovalbumin-stimulated IL-5 production was also increased in cultured splenocytes derived from fynKO mice relative to wild-type mice, whereas interferon-gamma levels were unchanged. Diminished concanavalin A-stimulated IL-4 levels from fynKO splenocytes were consistent with reduced serum immunoglobulin (Ig)E levels observed in sensitized/saline aerosol-challenged animals and may reflect defective natural killer 1.1(+) T cell development. Normalization of IgE levels in sensitized fynKO mice relative to wild-type mice occurred after repeat antigen challenge, which suggests a secondary source of IL-4. Overall, these data demonstrate fyn is a negative regulator of allergic: airway inflammation in mice because its absence promotes a shift to a T helper-2 phenotype that may reflect the kinase's role in T-cell receptor signaling.