CD5 Promotes IL-10 Production in Chronic Lymphocytic Leukemia B Cells through STAT3 and NFAT2 Activation
CD5 Promotes IL-10 Production in Chronic Lymphocytic Leukemia B Cells through STAT3 and NFAT2 Activation
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DOI：
10.4049/jimmunol.1003050
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发表时间：
2011-04-15
影响因子：
4.4
通讯作者：
Youinou, Pierre
中科院分区：
文献类型：
--
作者：
Garaud, Soizic;Morva, Ahsen;Youinou, Pierre
来自慢性淋巴细胞白血病 (CLL) 的 B 淋巴细胞显示一些包含已知外显子 1 (E1A) 的 CD5 转录物和包含新外显子 1 (E1B) 的其他 CD5 转录物。这些恶性B细胞以及用E1A-cd5的cDNA或E1B-cd5的cDNA转染的B细胞系产生IL-10，增加了CD5参与IL-10分泌的可能性。我们在来自 CLL 患者的 CD5(+) B 淋巴细胞以及 E1A-cd5 转染或 E1B-cd5 转染的 Jok 细胞中鉴定了参与这种产生的转录因子。 STAT3 通过丝氨酸 727 的磷酸化被激活，NFAT2 也通过其易位到细胞核中被激活。染色质免疫沉淀实验证实了 STAT3 的作用，并发现了 NFAT2 在 IL-10 产生中的作用。两种转录因子不仅与 Il-10 基因的增强子结合，而且与 Il-5 和 Il-13 基因的启动子结合。此外，用E1A-cd5或E1B-cd5转染B细胞系证实STAT3和NFAT2的激活受CD5调节。 IL-10、IL-5 和 IL-13 的产生以及这些细胞因子受体的表达也是如此。这个解释得到了两个实验的证实。首先，小干扰 RNA 下调 CD5 降低了 IL-10 的产生。在第二个实验中，将GFP-NFAT2基因转染至B淋巴细胞中，在CD5(+)B细胞中诱导NFAT2核易位，但在CD5(-)B细胞中则不诱导NFAT2核易位。因此，CD5 表达与 NFAT2 活性（以及轻微的 STAT3 活性）相关，表明 CD5 控制 IL-10 分泌。免疫学杂志，2011，186：4835-4844。
B lymphocytes from chronic lymphocytic leukemia (CLL) display some CD5 transcripts for CD5 containing the known exon 1 (E1A) and other CD5 transcripts containing the new exon 1 (E1B). These malignant B cells, as well as B cell lines transfected with cDNA for E1A-cd5 or with cDNA for E1B-cd5 produce IL-10, raising the possibility that CD5 participates in the secretion of IL-10. We identified transcription factors involved in this production in CD5(+) B lymphocytes from CLL patients and in E1A-cd5-transfected or E1B-cd5-transfected Jok cells. STAT3 is activated via phosphorylation of serine 727 but also NFAT2 through its translocation into the nucleus. Chromatin immunoprecipitation experiments confirmed the role of STAT3 and allowed the discovery of a role for NFAT2 in IL-10 production. Both transcription factors bind not only to the enhancer of the Il-10 gene but also to the promoter of the Il-5 and Il-13 genes. Furthermore, transfection of B cell lines with E1A-cd5 or E1B-cd5 established that activation of STAT3 and NFAT2 is regulated by CD5. The same holds true for the production of IL-10, IL-5, and IL-13 and the expression of the receptors for these cytokines. This interpretation was confirmed by two experiments. In the first, downregulation of CD5 by small interfering RNAs lowered the production of IL-10. In the second experiment, transfection of the GFP-NFAT2 gene into B lymphocytes induced nuclear translocation of NFAT2 in CD5(+) but not in CD5(-) B cells. Thus, CD5 expression is associated with NFAT2 activity (and mildly STAT3 activity), indicating that CD5 controls IL-10 secretion. The Journal of Immunology, 2011, 186: 4835-4844.