Small Rab GTPase Rab7b promotes megakaryocytic differentiation by enhancing IL-6 production and STAT3-GATA-1 association
Small Rab GTPase Rab7b promotes megakaryocytic differentiation by enhancing IL-6 production and STAT3-GATA-1 association
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小 Rab GTPase Rab7b 通过增强 IL-6 产生和 STAT3-GATA-1 关联促进巨核细胞分化
DOI：
10.1007/s00109-010-0689-z
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发表时间：
2011-02-01
影响因子：
4.7
通讯作者：
Cai, Zhen
中科院分区：
文献类型：
--
作者：
He, Donghua;Chen, Taoyong;Cai, Zhen
诱导人白血病细胞分化是治疗白血病的有效策略。然而，参与白血病细胞分化的分子机制尚未完全阐明。白细胞介素6（IL-6）是一种作用于多种细胞类型的多效性细胞因子，在造血过程中起重要作用。加塔结合蛋白1（加塔-1）是一种重要的转录因子，参与巨核细胞或红细胞的分化。在此，我们报道Rab 7 B，一种晚期内体/溶酶体定位的髓样小GT 4，通过增加核因子κB（NF-κB）依赖性IL-6的产生，随后增强活化的信号转导和转录激活因子3（STAT 3）与加塔-1的结合，促进佛波醇-12-肉豆蔻酸-13-乙酸酯（PMA）诱导的巨核细胞分化。以PMA诱导的白血病细胞向巨核系分化为模型，研究Rab 7 b在巨核系分化中的作用。我们发现Rab 7 B可以增强PMA诱导的巨核细胞标志物的上调、IL-6的产生和NF-κB的活化。NF-κB的抑制剂和IL-6或IL-6信号受体gp 130的中和抗体可以阻断Rab 7 B在巨核细胞分化中的作用。在Rab 7 b沉默的细胞中，PMA诱导的NF-κB活化、IL-6产生和巨核细胞分化受损。此外，我们证明，IL-6诱导的STAT 3的激活和随后的STAT 3与加塔-1的关联可能有助于PMA诱导和Rab 7 b介导的巨核细胞分化标志物的转录上调。提示Rab 7 B可能通过激活NF-κB和促进IL-6的产生而在巨核细胞的形成中发挥重要作用。我们的研究还表明，IL-6诱导的STAT 3与加塔-1的关联可能调节巨核细胞分化。
Induction of the differentiation of human leukemia cells is a useful strategy in treatment of human leukemia. However, the molecular mechanisms involved in leukemia cell differentiation have not been fully elucidated. Interleukin 6 (IL-6) is a pleiotropic cytokine acting on a variety of cell types, and plays important roles in hematopoiesis. GATA binding protein 1 (GATA-1) is an important transcription factor involved in either megakaryocytic or erythrocytic differentiation. Herein we report that Rab7b, a late endosome/lysosome-localized myeloid small GTPase, promotes phorbol-12-myristate-13-acetate (PMA)-induced megakaryocytic differentiation by increasing nuclear factor κB (NF-κB)-dependent IL-6 production and subsequently enhancing the association of activated signal transducer and activator of transcription 3 (STAT3) with GATA-1. By using PMA-induced megakaryocytic differentiation of leukemia cells as a model, we investigated the roles of Rab7b in megakaryocytic differentiation. We find that Rab7b can potentiate PMA-induced upregulation of megakaryocytic markers, production of IL-6, and activation of NF-κB. Inhibitor of NF-κB and neutralizing antibodies for IL-6 or the IL-6 signaling receptor gp130 can block the effects of Rab7b in megakaryocytic differentiation. In Rab7b-silenced cells, PMA-induced activation of NF-κB, IL-6 production, and megakaryocytic differentiation are impaired. Furthermore, we demonstrate that IL-6-induced activation of STAT3 and the subsequent association of STAT3 with GATA-1 may contribute to PMA-induced and Rab7b-mediated transcriptional upregulation of megakaryocytic differentiation markers. Therefore, our data suggest that Rab7b may play important roles in megakaryopoiesis by activating NF-κB and promoting IL-6 production. Our study also indicates that the IL-6-induced association of STAT3 with GATA-1 may regulate megakaryocytic differentiation.