The proinflammatory cytokine tumor necrosis factor (TNF) plays a central role in the host control of mycobacterial infections. Expression and release of TNF are tightly regulated, yet the molecular mechanisms that control the release of TNF by mycobacteria-infected host cells, in particular macrophages, are incompletely understood. Rab GTPases direct the transport of intracellular membrane-enclosed vesicles and are important regulators of macrophage cytokine secretion. Rab6b is known to be predominantly expressed in the brain where it functions in retrograde transport and anterograde vesicle transport for exocytosis. Whether it executes similar functions in the context of immune responses is unknown. Here we show that Rab6b is expressed by primary mouse macrophages, where it localized to the Golgi complex. Infection with Mycobacterium bovis bacille Calmette–Guérin (BCG) resulted in dynamic changes in Rab6b expression in primary mouse macrophages in vitro as well as in organs from infected mice in vivo. We further show that Rab6b facilitated TNF release by M. bovis BCG-infected macrophages, in the absence of discernible impact on Tnf messenger RNA and intracellular TNF protein expression. Our observations identify Rab6b as a positive regulator of M. bovis BCG-induced TNF trafficking and secretion by macrophages and positions Rab6b among the molecular machinery that orchestrates inflammatory cytokine responses by macrophages.

中文翻译：

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Rab6b 定位于鼠巨噬细胞中的高尔基复合体并促进肿瘤坏死因子释放以响应分枝杆菌感染

促炎细胞因子肿瘤坏死因子 (TNF) 在分枝杆菌感染的宿主控制中起着核心作用。TNF 的表达和释放受到严格调控，但控制分枝杆菌感染宿主细胞（尤其是巨噬细胞）释放 TNF 的分子机制尚不完全清楚。Rab GTPases 指导细胞内膜封闭囊泡的运输，是巨噬细胞细胞因子分泌的重要调节剂。已知 Rab6b 主要在大脑中表达，它在逆行运输和顺行囊泡运输中发挥作用，用于胞吐作用。它是否在免疫反应的背景下执行类似的功能尚不清楚。在这里，我们展示了 Rab6b 由原代小鼠巨噬细胞表达，在那里它定位于高尔基复合体。感染牛分枝杆菌卡介苗（BCG）导致体外原代小鼠巨噬细胞以及体内感染小鼠器官中 Rab6b 表达的动态变化。我们进一步表明，在对Tnf信使 RNA 和细胞内 TNF 蛋白表达没有明显影响的情况下，Rab6b 促进了牛分枝杆菌BCG 感染的巨噬细胞释放TNF。我们的观察结果表明，Rab6b 是牛分枝杆菌BCG 诱导的巨噬细胞 TNF 运输和分泌的正调节剂，并将 Rab6b 置于协调巨噬细胞炎症细胞因子反应的分子机制中。