Defective PTEN regulation contributes to B cell hyperresponsiveness in systemic lupus erythematosus
| Autor: | Xuetao Cao, Yang Li, Xuan Zhang, Wei He, Yan Xia Ye, Xin Li, Fengchun Zhang, Fu Lin Tang, Hua Chen, Xiao Feng Zeng, Jing Wen Niu, Xin You, Peter E. Lipsky, Xiangni Wu, Li Dan Zhao |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Adolescent B-cell receptor Molecular Sequence Data Plasma Cells Down-Regulation Lymphocyte Activation Young Adult immune system diseases microRNA medicine PTEN Humans Lupus Erythematosus Systemic Calcium Signaling Phosphorylation skin and connective tissue diseases STAT3 B cell Cell Proliferation B-Lymphocytes Lupus erythematosus CD40 biology Base Sequence Interleukins PTEN Phosphohydrolase Cell Differentiation General Medicine Cell sorting medicine.disease ADP-ribosyl Cyclase 1 Up-Regulation MicroRNAs Proteinuria medicine.anatomical_structure Gene Expression Regulation biology.protein Cancer research Female Proto-Oncogene Proteins c-akt |
| Zdroj: | Science translational medicine. 6(246) |
| ISSN: | 1946-6242 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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