Acute cytokine response to systemic adenoviral vectors in mice is mediated by dendritic cells and macrophages
Acute cytokine response to systemic adenoviral vectors in mice is mediated by dendritic cells and macrophages
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DOI：
10.1006/mthe.2001.0329
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发表时间：
2001-05-01
影响因子：
12.4
通讯作者：
Wilson, JM
中科院分区：
文献类型：
--
作者：
Zhang, Y;Chirmule, N;Wilson, JM
我们研究了静脉注射腺病毒载体（Ad）后小鼠分泌炎性细胞因子的细胞基础。静脉注射表达 Ad 的大肠杆菌 P-半乳糖苷酶 (Ad-lacZ) 后 6 小时即可检测到血清炎症细胞因子，包括白介素 6 (IL-6)、IL-12 和肿瘤坏死因子 α (TNF-α)。静脉输注后 1 小时，Ad-lacZ 很容易在脾边缘区积聚，其中树突状细胞 (DC) 和巨噬细胞在 6 小时内被转导和激活。流式细胞术分析表明，脾 DC 上 ia 和 CD86 抗原的表达显着增强，表明它们在体内被 Ad-lacZ 激活。离体培养后，这些早期激活的脾 DC 自发产生高水平的 IL-6 和 IL-12。相比之下，激活的脾巨噬细胞仅自发分泌 IL-6。体内消除组织巨噬细胞和脾DC显着减少了IL-12、IL-6和TNF-α的早期释放，并显着阻断了体内对Ad和转基因产物的特异性细胞免疫反应。我们的研究结果表明，DC 和巨噬细胞的优先激活可能是 Ad 触发小鼠体内急性炎症反应的原因。此外，DC 和巨噬细胞在这一过程中可能发挥不同的作用，因为它们产生不同模式的炎症细胞因子的能力。
We investigated the cellular basis for secretion of inflammatory cytokines in mice following intravenous administration of adenoviral vectors (Ad). Serum inflammatory cytokines including interleukin-6 (IL-6), IL-12, and tumor necrosis factor-alpha (TNF-alpha) were detected as early as 6 h following intravenous injection of Ad-expressing Escherichia coli P-galactosidase (Ad-lacZ). Ad-lacZ readily accumulated in the splenic marginal zone 1 h after intravenous infusion, where both dendritic cells (DCs) and macrophages were transduced and activated within 6 h. Flow cytometric analyses showed that the expression of ia and CD86 antigens was markedly enhanced on splenic DCs indicating their activation in vivo by Ad-lacZ. Upon ex vivo culture, these early-activated splenic DCs spontaneously produced high levels of IL-6 and IL-12. By contrast, activated splenic macrophages spontaneously secreted only IL-6. Elimination of tissue macrophages and splenic DCs in vivo considerably reduced the early release of IL-12, IL-6, and TNF-alpha and significantly blocked the specific cellular immune response to Ad and the transgene product in vivo. Our findings indicate that preferential activation of DCs and macrophages may account for Ad-triggered acute inflammatory response in vivo in mice. Moreover, DCs and macrophages may play different roles in this process in terms of their abilities to produce distinct patterns of inflammatory cytokines.