Hardenberg Gijs, Planelles Lourdes, Schwarte Carla M, van Bostelen Liesbeth, Le Huong Tran, Hahne Michael, Medema Jan Paul
Laboratory of Experimental Oncology and Radiobiology, Academic Medical Center, Amsterdam, The Netherlands.
Eur J Immunol. 2007 Oct;37(10):2900-11. doi: 10.1002/eji.200737210.
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.
增殖诱导配体（APRIL）和属于肿瘤坏死因子家族的B细胞活化因子（BAFF/BLyS）已被证明参与非胸腺依赖（TI）B细胞应答中的IgA类别转换重组。树突状细胞（DC）被认为通过向B细胞提供包括APRIL和BAFF在内的细胞因子来调节TI B细胞应答中的Ig类别转换。因此，我们着手分析人单核细胞衍生的DC（moDC）对APRIL和BAFF表达的调控。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和聚肌胞苷酸（poly I:C）刺激可特异性诱导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蛋白激酶受体（PKR）的激活导致的，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的信号整合是由翻译修饰调节的，并提示APRIL在TI B细胞对病毒感染的应答中起作用。
