Double-stranded RNA induces the synthesis of specific chemokines by bronchial epithelial cells
Double-stranded RNA induces the synthesis of specific chemokines by bronchial epithelial cells
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DOI：
10.1165/rcmb.2002-0055oc
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发表时间：
2003-06-01
影响因子：
6.4
通讯作者：
Busse, WW
中科院分区：
文献类型：
--
作者：
Gern, JE;French, DA;Busse, WW
病毒诱导的呼吸道上皮细胞分泌促炎趋化因子(如活化调节、正常T细胞表达和分泌[RANTES]、白介素[IL]-8)有助于通过促进炎症细胞募集来启动抗病毒反应和呼吸道炎症。为了明确病毒诱导趋化因子分泌的机制，将多脱氧肌苷脱氧胞苷酸(合成双链RNA)、鼻病毒双链RNA或单链RNA(单链RNA)转染或孵育未转化的支气管上皮细胞，并测定其分泌趋化因子的能力。DsRNA可显著增加RANTES和IL-8的分泌，但不能促进嗜酸性粒细胞趋化因子或巨噬细胞炎性蛋白-1α的分泌。机制上，dsRNA诱导和激活dsRNA依赖的蛋白激酶(PKR)，并激活核因子-kappaB和p38丝裂原激活的蛋白激酶。此外，PKR抑制剂2-氨基嘌呤显著抑制dsRNA诱导的RANTES和IL-8的分泌，而p38丝裂原活化蛋白激酶抑制剂SB203580抑制dsRNA诱导的IL-8，但不抑制RANTES。这些发现表明，dsRNA选择性地诱导IL-8和RANTES等趋化因子的分泌，并参与这一过程中的dsRNA敏感信号蛋白。此外，这些数据表明，这可能是病毒(如鼻病毒、呼吸道合胞病毒、流感病毒)选择性分泌趋化因子的重要机制，这些病毒在复制过程中合成dsRNA。
Virus-induced secretion of proinflammatory chemokines (e.g., regulated on activation, normal T cells expressed and secreted [RANTES], interleukin [IL]-8) by airway epithelial cells helps to initiate antiviral responses and airway inflammation by enhancing inflammatory cell recruitment. To define mechanisms for virus-induced chemokine secretion, monolayers of nontransformed bronchial epithelial cells were transfected or incubated with polydeoxyinosinic-deoxycytidylic acid (synthetic double-stranded [ds] RNA), rhinovirus dsRNA, or single-stranded RNA (ssRNA), and the secretion of selected chemokines was determined. Transfection or incubation with dsRNA, but not ssRNA, significantly enhanced secretion of RANTES and IL-8, but not eotaxin or macrophage inflammatory protein-1alpha. Mechanistically, dsRNA induced and activated dsRNA-dependent protein kinase (PKR), and activated nuclear factor-kappaB and p38 mitogen-activated protein kinase. Furthermore, the PKR inhibitor 2-aminopurine significantly blocked dsRNA-induced RANTES and IL-8 secretion, whereas the p38 mitogen-activated protein kinase inhibitor SB203580 suppressed dsRNA-induced IL-8, but not RANTES. These findings indicate that dsRNA selectively induce the secretion of chemokines such as IL-8 and RANTES, and implicate dsRNA-sensitive signaling proteins in this process. Moreover, these data suggest that this may be an important mechanism for the selective secretion of chemokines by viruses (e.g., rhinovirus, respiratory syncytial virus, influenza) that synthesize dsRNA during replication.