PTEN公司
B细胞
张力素
癌症研究
蛋白激酶B
免疫学
PI3K/AKT/mTOR通路
生物
信号转导
细胞生物学
抗体
作者
Xiang Ni Wu,Yan Xia Ye,Jing Niu,Yang Li,Xin Li,Xin You,Hua Chen,Zhao Li,Xianwei Zeng,Feng Chun Zhang,Fu-lin Tang,He Wang,Xue Cao,Xuan Zhang,Peter E. Lipsky
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2014-07-23
卷期号:6 (246)
被引量:131
标识
DOI:10.1126/scitranslmed.3009131
摘要
PTEN regulates normal signaling through the B cell receptor (BCR). In systemic lupus erythematosus (SLE), enhanced BCR signaling contributes to increased B cell activity, but the role of PTEN in human SLE has remained unclear. We performed fluorescence-activated cell sorting analysis in B cells from SLE patients and found that all SLE B cell subsets, except for memory B cells, showed decreased expression of PTEN compared with B cells from healthy controls. Moreover, the level of PTEN expression was inversely correlated with disease activity. We then explored the mechanisms governing PTEN regulation in SLE B cells. Notably, in normal but not SLE B cells, interleukin-21 (IL-21) induced PTEN expression and suppressed Akt phosphorylation induced by anti-immunoglobulin M and CD40L stimulation. However, this deficit was not primarily at the signaling or the transcriptional level, because IL-21-induced STAT3 (signal transducer and activator of transcription 3) phosphorylation was intact and IL-21 up-regulated PTEN mRNA in SLE B cells. Therefore, we examined the expression of candidate microRNAs (miRs) that could regulate PTEN: SLE B cells were found to express increased levels of miR-7, miR-21, and miR-22. These miRs down-regulated the expression of PTEN, and IL-21 stimulation increased the expression of miR-7 and miR-22 in both normal and SLE B cells. Indeed, a miR-7 antagomir corrected PTEN-related abnormalities in SLE B cells in a manner dependent on PTEN. Therefore, defective miR-7 regulation of PTEN contributes to B cell hyperresponsiveness in SLE and could be a new target of therapeutic intervention.
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