SHP-1缺失的肥大细胞在小鼠肺过敏性炎症中的作用
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摘要
含有Src同源结构域的蛋白酪氨酸磷酸酶1(SHP-1)缺失的小鼠过敏性哮喘表型是白细胞介素13(IL-13)和转录因子STAT6依赖的。它是一种辅助性T淋巴(Th)2类细胞应答,其分子机制并没有完全清楚。我们推测SHP-1的缺失导致了肥大细胞功能失调和细胞产物增加、介质和Th2类细胞因子的释放,从而产生过敏性哮喘表现。我们用mev小鼠骨髓源性肥大细胞(bone marrow derived mast cells, BMMC)检测了SHP-1基因对肥大细胞的分化、存活率以及对刺激的功能反应机能的调节。评测了肥大细胞缺失的KitW-Sh基因型背景下的mev小鼠肺功能表型的变化。
研究中发现SHP-1是肥大细胞分化、成熟及增殖等功能的重要调节因子,在SHP-1缺陷的情况下,肥大细胞是分泌Th2类细胞因子,促进过敏性哮喘表型发生的主要细胞。
mev小鼠的骨髓中,成熟的肥大细胞比例明显高于野生型小鼠。这种差异可以一直持续到细胞培养的第16天。但在随后,mev小鼠和野生型小鼠的这种差异逐渐消失,而且mev基因型小鼠细胞的增殖趋于平缓,野生型小鼠细胞的增殖却明显加速。RT-PCR实验结果显示Bcl-2基因在mev小鼠的BMMC中明显上调,但是流式细胞仪检测表明SHP-1缺陷小鼠的BMMC不能抵抗培养环境中不加生长因子所诱导的凋亡。这些结果提示SHP-1的调节不能产生内源性的抗凋亡信号但能增强那些被生长因子启动的效应。
研究中,我们评价了SHP-1在调节肥大细胞应答于氧化剂刺激和细菌产物脂多糖(LPS)刺激后的细胞因子应答中的功能。结果显示：mev小鼠BMMC的IL-4和IL-13表达明显增加,而γ干扰素(IFN-γ)无变化,且这一变化可被抗氧化剂乙酰半胱氨酸(NAC)阻断。同样,mev小鼠的BMMC应答于LPS刺激后,产生的IL-13明显增高,而不受过氧化氢(H2O2)或NAC影响。提示,ROS和核因子κB(NF-κB)没有参与到这一活化过程。进一步我们发现,激酶抑制剂Gleevec对LPS刺激肥大细胞产生的IL-13没有明显影响,表明该过程是非c-Kit依赖的。
我们证实用免疫球蛋白Fc段受体I (FcεRI)刺激后,SHP-1能结合T细胞激活交联子2(LAT2),肥大细胞SHP-1缺陷可导致LAT2的磷酸化明显增加,这与肥大细胞活性的增加完全一致。
为了检测体内SHP-1的下调是否也能影响肥大细胞的功能,我们检测了肺部的肥大细胞的数量和活性以及在mev小鼠过敏性哮喘表型中的作用。这些研究显示,SHP-1缺陷可导致肺部肥大细胞数目的增加,更重要的是在未刺激和应答于刺激后,均可明显增加肺和脾脏的肥大细胞的活性,释放更多的介质,产生更多的Th2类细胞因子。
在肥大细胞缺陷的KitW-Sh遗传背景下的mev小鼠,其气道炎症明显减轻,肺病理情况转好,IL-13和趋化因子的量减少。
以上发现证明SHP-1在肥大细胞的发育和功能作用方面是重要的调节因子,SHP-1缺失的肥大细胞能大量产生Th2类细胞因子并在肺部启动过敏性免疫应答。
Phosphatase SHP-1 deficient mice display an allergic asthma phenotype that is largely IL-13 and STAT6 dependent. The cell types responsible for the Th2 phenotype have not been identified. We hypothesized that SHP-1 deficiency leads to mast cell dysregulation and increased production and release of mediators and Th2 cytokines, leading to the allergic asthma phenotype. We examined SHP-1 regulation of mast cell differentiation, survival, and functional responses to stimulation using bone marrow derived mast cells from viable motheaten (mev) mice. We assessed pulmonary phenotypical changes in mev mice on mast cell deficient KitW-Sh genetic background. The results show that SHP-1 deficiency leads to increased differentiation and survival, but reduced proliferation, of mast cells. SHP-1 deficient mast cells produce and release increased amounts of mediators and Th2 cytokines IL-4 and IL-13, spontaneously and in response to H2O2, LPS, and FcεRI cross-linking, involving c-Kit-dependent and independent processes. The FcsRI signaling leads to binding of SHP-1 to LAT2 and enhanced LAT2 phosphorylation in mev BMMC. Furthermore, the number of mast cells in the lung tissue of mev mice is increased and mast cell production and release of Th2 cytokines are distinctly increased upon FcεRI stimulation. When backcrossed to the KitW-Sh background mev mice have markedly reduced pulmonary inflammation and Th2 cytokine production. These findings demonstrate that SHP-1 is a critical regulator of mast cell development and function and that SHP-1 deficient mast cells are able to produce increased Th2 cytokines and to initiate allergic inflammatory responses in the lung.
研究中发现SHP-1是肥大细胞分化、成熟及增殖等功能的重要调节因子,在SHP-1缺陷的情况下,肥大细胞是分泌Th2类细胞因子,促进过敏性哮喘表型发生的主要细胞。
mev小鼠的骨髓中,成熟的肥大细胞比例明显高于野生型小鼠。这种差异可以一直持续到细胞培养的第16天。但在随后,mev小鼠和野生型小鼠的这种差异逐渐消失,而且mev基因型小鼠细胞的增殖趋于平缓,野生型小鼠细胞的增殖却明显加速。RT-PCR实验结果显示Bcl-2基因在mev小鼠的BMMC中明显上调,但是流式细胞仪检测表明SHP-1缺陷小鼠的BMMC不能抵抗培养环境中不加生长因子所诱导的凋亡。这些结果提示SHP-1的调节不能产生内源性的抗凋亡信号但能增强那些被生长因子启动的效应。
研究中,我们评价了SHP-1在调节肥大细胞应答于氧化剂刺激和细菌产物脂多糖(LPS)刺激后的细胞因子应答中的功能。结果显示：mev小鼠BMMC的IL-4和IL-13表达明显增加,而γ干扰素(IFN-γ)无变化,且这一变化可被抗氧化剂乙酰半胱氨酸(NAC)阻断。同样,mev小鼠的BMMC应答于LPS刺激后,产生的IL-13明显增高,而不受过氧化氢(H2O2)或NAC影响。提示,ROS和核因子κB(NF-κB)没有参与到这一活化过程。进一步我们发现,激酶抑制剂Gleevec对LPS刺激肥大细胞产生的IL-13没有明显影响,表明该过程是非c-Kit依赖的。
我们证实用免疫球蛋白Fc段受体I (FcεRI)刺激后,SHP-1能结合T细胞激活交联子2(LAT2),肥大细胞SHP-1缺陷可导致LAT2的磷酸化明显增加,这与肥大细胞活性的增加完全一致。
为了检测体内SHP-1的下调是否也能影响肥大细胞的功能,我们检测了肺部的肥大细胞的数量和活性以及在mev小鼠过敏性哮喘表型中的作用。这些研究显示,SHP-1缺陷可导致肺部肥大细胞数目的增加,更重要的是在未刺激和应答于刺激后,均可明显增加肺和脾脏的肥大细胞的活性,释放更多的介质,产生更多的Th2类细胞因子。
在肥大细胞缺陷的KitW-Sh遗传背景下的mev小鼠,其气道炎症明显减轻,肺病理情况转好,IL-13和趋化因子的量减少。
以上发现证明SHP-1在肥大细胞的发育和功能作用方面是重要的调节因子,SHP-1缺失的肥大细胞能大量产生Th2类细胞因子并在肺部启动过敏性免疫应答。
Phosphatase SHP-1 deficient mice display an allergic asthma phenotype that is largely IL-13 and STAT6 dependent. The cell types responsible for the Th2 phenotype have not been identified. We hypothesized that SHP-1 deficiency leads to mast cell dysregulation and increased production and release of mediators and Th2 cytokines, leading to the allergic asthma phenotype. We examined SHP-1 regulation of mast cell differentiation, survival, and functional responses to stimulation using bone marrow derived mast cells from viable motheaten (mev) mice. We assessed pulmonary phenotypical changes in mev mice on mast cell deficient KitW-Sh genetic background. The results show that SHP-1 deficiency leads to increased differentiation and survival, but reduced proliferation, of mast cells. SHP-1 deficient mast cells produce and release increased amounts of mediators and Th2 cytokines IL-4 and IL-13, spontaneously and in response to H2O2, LPS, and FcεRI cross-linking, involving c-Kit-dependent and independent processes. The FcsRI signaling leads to binding of SHP-1 to LAT2 and enhanced LAT2 phosphorylation in mev BMMC. Furthermore, the number of mast cells in the lung tissue of mev mice is increased and mast cell production and release of Th2 cytokines are distinctly increased upon FcεRI stimulation. When backcrossed to the KitW-Sh background mev mice have markedly reduced pulmonary inflammation and Th2 cytokine production. These findings demonstrate that SHP-1 is a critical regulator of mast cell development and function and that SHP-1 deficient mast cells are able to produce increased Th2 cytokines and to initiate allergic inflammatory responses in the lung.
引文
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