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J Immunol：TNF反向信号调节炎症反应分子机制

2016-01-11 佚名 生物谷

炎症机制TNF-a
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TNF-a是一类典型的炎性细胞因子，它的前体是一类II型跨膜蛋白（mTNF-a）。成熟的TNF-a能够识别细胞表面的TNF-R1以及TNF-R2，从而使得该类受体的激活与三聚化。类似的，TNF-a前体有两类截然不同的功能：由于mTNF-a在未结合受体的情况下是天然的三聚化结构，一方面它可以像成熟的TNF-a一样与TNF-R结合产生下游信号，另一方面这一结合也可以使其将受体信号反向传递至配体细胞中（

TNF-a是一类典型的炎性细胞因子，它的前体是一类II型跨膜蛋白（mTNF-a）。成熟的TNF-a能够识别细胞表面的TNF-R1以及TNF-R2，从而使得该类受体的激活与三聚化。类似的，TNF-a前体有两类截然不同的功能：由于mTNF-a在未结合受体的情况下是天然的三聚化结构，一方面它可以像成熟的TNF-a一样与TNF-R结合产生下游信号，另一方面这一结合也可以使其将受体信号反向传递至配体细胞中（即相反方向）。之前的研究已经发现mTNF-a的反向信号能够干预LPS对巨噬细胞的激活作用，其中的关键步骤包括ERK的激活。然而，其中的分子机制并不清楚。在最近的一项研究中，来自希腊Debrecen大学的Zsuzsa Szondy课题组阐释了TNF-a反向信号的最新分子机制。相关结果发表在最新一期的Journal of Immunology杂志上。

 
首先，作者希望了解天然免疫细胞表面mTNF-a的表达情况。他们选择了小鼠原代骨髓巨噬细胞以及RAW264.7细胞系进行研究。结果显示，在未激活状态下，两类细胞表面TNF-a有一个本底水平的表达，在受到LPS刺激后，这一表达水平会显著提高。之后，他们发现mTNFa的信号会使得下游MKK3/6、PI3K、MAPK、JNK等激酶的激活。
 
进一步，作者通过real-time PCR的方法证明mTNF-a激活后会使巨噬细胞产生TGF-b。而通过小分子抑制剂分别阻断了下游JNK、ERK、MAPK等激酶的活性。结果显示，在JNK活性被抑制的情况下，mTNF-a引发的TGF-b释放受到了明显的抑制，但p38 MAPK的抑制则没有明显的影响。这一结果说明JNK在mTNF-a的信号传递过程中具有重要的作用。之后，作者证明了mTNF-a通过诱导产生TGF-b能够抑制LPS对巨噬细胞的激活作用。
 
由于临床上有许多针对TNF-a的药物，涵盖了包括肠炎、关节炎等在内的多种免疫疾病。但是这些药物在调节炎症反应的效果上却千差万别。作者根据上述实验的结果推测这一差异可能与TGF-b的含量有一定关系。通过体外培养并刺激人员巨噬细胞，同时加入不同类型的药物。结果显示：那些临床上效果好的药物通常能够引发较多的TGF-b的产生。

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    2016-01-13 lsj628

    #炎症反应#

    0

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    2016-01-13 snowpeakxu

    #TNF#

    0

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    2016-01-12 huangshang9812

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    2016-01-12 老段

    信号

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    2016-01-11 不着调的小师兄

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一直到最近，科学家们仍认为阿尔茨海默症干扰了免疫系统，但是小鼠身上的一项新的研究显示，脑部感染或导致了阿尔茨海默症的发生，研究表明阻断调节免疫细胞的一种蛋白或是停止这种脑萎缩性疾病进展的一种方法，该研究结果在线发表于Brain。