Mouse splenic B lymphocyte activation using different activation stimuli induces in vitro splicing of tumor necrosis factor-alpha nuclear pre-mRNA.
Mouse splenic B lymphocyte activation using different activation stimuli induces in vitro splicing of tumor necrosis factor-alpha nuclear pre-mRNA.
复制标题
使用不同激活刺激的小鼠脾 B 淋巴细胞激活诱导肿瘤坏死因子-α 核前 mRNA 的体外剪接。
DOI：
10.1016/j.molimm.2005.04.010
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发表时间：
2006
影响因子：
3.6
通讯作者：
Parnes,JaneR
中科院分区：
文献类型：
--
作者：
Li,Yi-YangYvonne;Yang,Yang;Bao,Ming;Edwards3rd,CarlK;Parnes,JaneR
在过去的十年里，肿瘤坏死因子α的多效性引起了人们对其在炎症性疾病和自身免疫性疾病中的生理和病理作用的极大关注。然而，在T和B淋巴细胞等免疫细胞中，肿瘤坏死因子α的产生是如何在转录和翻译水平上进行调节的，目前还知之甚少。我们先前的研究表明，在静止的T细胞中存在未剪接的肿瘤坏死因子α的“前mRNAs”。与单核巨噬细胞(包括不同谱系的巨噬细胞(Mα)和树突状细胞(DC))产生的肿瘤坏死因子α相比，T细胞的激活对肿瘤坏死因子ϕ的产生是独特和必要的。在这项研究中，我们进一步证明了静息状态的小鼠B细胞也含有预先存在的肿瘤坏死因子α基因。B细胞活化的生理过程：(1)B细胞受体或CD_(40)的交联性；(2)脂多糖或PMA+离子霉素处理，在体外诱导肿瘤坏死因子α基因的剪接。与活化的T细胞相比，肿瘤坏死因子α在B细胞中的剪接动力学反应要慢得多。使用众所周知的激酶抑制剂的研究表明，当通过bcr刺激时，肿瘤坏死因子α的剪接需要MAPK和蛋白激酶C。这些研究表明，活化的B细胞和活化的T细胞产生肿瘤坏死因子α的调控不同，这些差异可能允许在各种自身免疫性疾病中选择性地抑制肿瘤坏死因子α，这取决于所选择的抗肿瘤坏死因子α治疗的作用机制。
The pleiotropic functions of tumor necrosis factor-alpha (TNFα) have brought considerable attention in the past decade to its physiological and pathological roles in inflammatory and autoimmune diseases. However, little is known about how the production of TNFα is regulated at the transcriptional and translational levels in immune cells such as T and B lymphocytes. Our previous study demonstrated that unspliced “pre-mRNA” of TNFα is present in resting T cells. Initiation of splicing of TNFα pre-mRNA to mature mRNA requires T cell activation, which is unique and necessary for TNFα production when compared to its production in mononuclear phagocytes, including different lineages of macrophages (Mϕ) and dendritic cells (DC). In this study, we further demonstrate that resting mouse B cells also contain pre-existing TNFα mRNA. The physiological process of B cell activation induced by (1) either the cross-linking of the B cell receptor (BCR) or CD40, (2) treatment with LPS, or PMA plus ionomycin, induces TNFα mRNA splicing in vitro. The kinetic response of TNFα splicing in B cells is much slower when compared to that in activated T cells. Studies using well-known kinase inhibitors demonstrated that MAP kinase kinase (MEK) and protein kinase C (PKC) are required for TNFα splicing upon stimulation through the BCR. These studies demonstrate that the production of TNFα in activated B cells is regulated differently than in activated T cells, and these differences may allow for the selective inhibition of TNFα in various autoimmune diseases depending on the mechanism of action of the selected anti-TNFα therapy.