Specific TLR ligands regulate APRIL secretion by dendritic cells in a PKR-dependent manner
Specific TLR ligands regulate APRIL secretion by dendritic cells in a PKR-dependent manner
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DOI：
10.1002/eji.200737210
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发表时间：
2007-10-01
影响因子：
5.4
通讯作者：
Medema, Jan Paul
中科院分区：
文献类型：
--
作者：
Hardenberg, Gijs;Planelles, Lourdes;Medema, Jan Paul
属于 TNF 家族的增殖诱导配体 (APRIL) 和 B 细胞激活因子 (BAFF/BLyS) 与胸腺非依赖性 (TI) B 细胞反应中的 IgA 类转换重组有关。树突状细胞 (DC) 被认为通过向 B 细胞提供细胞因子（包括 APRIL 和 BAFF）来调节 TI B 细胞反应中的 Ig 类别转换。因此，我们开始分析人单核细胞来源的 DC (moDC) 对 APRIL 和 BAFF 表达的调节。我们观察到moDC产生并分泌APRIL，但未检测到BAFF的表达。重要的是，用Toll样受体配体CpG和poly I:C刺激可以特异性诱导APRIL的产生，而其他Toll样受体配体则无效。 APRIL 的增加依赖于翻译，但令人惊讶的是不依赖于转录。相反，APRIL 产生和分泌的增强是由于蛋白激酶受体 (PKR) 的激活所致，因为它被 PKR 的特异性抑制剂 2-氨基嘌呤完全抑制。这表明 CpG 和 Poly I:C 对 APRIL 的特异性诱导以及 PKR 的信号整合受到翻译修饰的调节，并暗示 APRIL 在 TI B 细胞对病毒感染的反应中的作用。
A proliferation inducing ligand (APRIL) and B cell activating factor belonging to the TNF family (BAFF/BLyS) have been implicated in IgA class switch recombination in thymus-independent (TI) B cell responses. Dendritic cells (DC) are thought to regulate Ig class switching in TI B cell responses by providing B cells with cytokines, including APRIL and BAFF. We therefore set out to analyze the regulation of APRIL and BAFF expression by human monocyte-derived DC (moDC). We observed that moDC produce and secrete APRIL, but could not detect expression of BAFF. Importantly, stimulation with the Toll-like receptor ligands CpG and poly I:C specifically induced APRIL production, while other Toll-like receptor ligands were ineffective. The increase in APRIL was dependent on translation, but surprisingly not transcription. Instead, enhanced APRIL production and secretion resulted from activation of protein kinase receptor (PKR), as it was completely inhibited by the specific inhibitor of PKR, 2-aminopurine. This suggests that the specific induction of APRIL by CpG and poly I: C, and the signal integration by PKR, are regulated by translational modification and hint at a role for APRIL in the TI B cell response to viral infections.