Activation of mast cells by double-stranded RNA: Evidence for activation through Toll-like receptor 3
Activation of mast cells by double-stranded RNA: Evidence for activation through Toll-like receptor 3
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DOI：
10.1016/j.jaci.2004.03.049
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发表时间：
2004-07-01
影响因子：
14.2
通讯作者：
Metcalfe, DD
中科院分区：
文献类型：
--
作者：
Kulka, M;Alexopoulou, L;Metcalfe, DD
背景：虽然肥大细胞明显参与了细菌的先天免疫反应，但其对病毒感染的应答能力尚不清楚。目的：鉴于肥大细胞在炎症部位增加，并位于可能发生入侵病毒暴露的表面，我们探索了肥大细胞在接触病毒和合成病毒双链RNA的模拟物多肌苷多胞苷(PolyI：C)后产生包括I型IFN在内的细胞因子的能力，并对参与其中的受体进行了鉴定。方法：人外周血来源的MC和2个MC系，变态反应性疾病实验室MC系和人MC系1，用病毒和PolyI：C刺激，检测细胞因子的产生、脱颗粒和信号通路的激活。由于PolyI：C是Toll样受体(TLR)-3的配体，因此也分析了人MCs中TLR的表达。结果：病毒和PolyI：C诱导产生干扰素α和干扰素β。与其他TLR配体(脂多糖、肽聚糖、CpG-A或鞭毛蛋白)相比，PolyI：C不能诱导肿瘤坏死因子、IL-1β、IL-5或GMCSF的产生。干扰素-α的产生涉及核因子-kappaB、p38、C-jun氨基末端激酶和丝裂原活化蛋白激酶。RT-PCR和Western印迹分析证实所有MC均表达TLR-3。人培养的MC也表达TLR-1、TLR-2、TLR-4、TLR-5、TLR-6、TLR-7和TLR-9。抗TLR-3抗体显著降低干扰素-α的产生。TLR-3基因敲除小鼠骨髓来源的MC对PolyI：C具有消融反应。结论：小鼠和人MC在暴露于双链RNA和/或病毒后产生I型IFN，前者通过与TLR-3的特异性相互作用而产生。这些数据表明，MC通过产生I型干扰素促进了对病毒感染的先天免疫反应。
Background: Although mast cells (MCs) have been clearly implicated in innate immune responses involving bacteria, their ability to respond to viral infection is less clear.Objective: Given that MCs increase at sites of inflammation and are located at surfaces where exposure to invading viruses may occur, we explored the ability of MCs to produce cytokines including type I IFNs after exposure to viruses and to polyinosine-polycytidylic acid (polyI:C), a synthetic mimic of viral double-stranded RNA, and characterized the receptors involved, if any.Methods: Human peripheral blood-derived cultured MCs and 2 MC lines, Laboratory of Allergic Disease MC line and human MC line 1, were stimulated with viruses and polyI:C, and cytokine production, degranulation, and signaling pathway activation were examined. Because polyI:C is a ligand for Toll-like receptor (TLR)-3, human MCs were also analyzed for TLR expression.Results: Viruses and polyI:C induced IFN-alpha and IFN-beta production. PolyI:C did not induce TNF, IL-1beta, IL-5, or GMCSF production, in contrast with other TLR ligands (LPS, peptidoglycan, CpG-A, or flagellin). IFN-alpha production involved nuclear factor-kappaB, p38, and C-Jun NH2-terminal kinase and mitogen-activated protein kinase. RT-PCR and Western blot analysis confirmed expression of TLR-3 by all MCs. Human cultured MCs also expressed TLR-1, TLR-2, TLR-4, TLR-5, TLR-6, TLR-7 and TLR-9. Antibodies to TLR-3 significantly decreased IFN-a production. Bone marrow-derived MCs from TLR-3 knockout mice showed an ablated response to polyI:C.Conclusions: Murine and human MCs produce type I IFNs after exposure to double-stranded RNA and/or virus, the former via specific interactions with TLR-3. These data suggest that MCs contribute to innate immune responses to viral infection via the production of type I IFNs.