Defective PTEN regulation contributes to B cell hyperresponsiveness in systemic lupus erythematosus

被引:137
作者
Wu, Xiang-ni [1 ,2 ]
Ye, Yan-xia [1 ,2 ]
Niu, Jing-wen [1 ,2 ]
Li, Yang [1 ,2 ]
Li, Xin [1 ,2 ]
You, Xin [1 ,2 ]
Chen, Hua [1 ,2 ]
Zhao, Li-dan [1 ,2 ]
Zeng, Xiao-feng [1 ,2 ]
Zhang, Feng-chun [1 ,2 ]
Tang, Fu-lin [1 ,2 ]
He, Wei [3 ,4 ]
Cao, Xue-tao [3 ,4 ]
Zhang, Xuan [1 ,2 ]
Lipsky, Peter E. [1 ,2 ,5 ]
机构
[1] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Rheumatol & Clin Immunol, Beijing 100730, Peoples R China
[2] Peking Union Med Coll, Beijing 100730, Peoples R China
[3] Peking Union Med Coll, Sch Basic Med, Dept Immunol, Beijing 100005, Peoples R China
[4] Chinese Acad Med Sci, Inst Basic Med Sci, Beijing 100005, Peoples R China
[5] NIAMSD, NIH, Bethesda, MD 20892 USA
基金
中国国家自然科学基金;
关键词
PROTEIN-KINASE B; TUMOR-SUPPRESSOR; INTERLEUKIN-21; RECEPTOR; PHOSPHOINOSITIDE; 3-KINASE; SIGNALING PATHWAY; ANTIGEN RECEPTOR; IL-21; ACTIVATION; EXPRESSION; IDENTIFICATION;
D O I
10.1126/scitranslmed.3009131
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
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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页数:12
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