Laza-Stanca Vasile, Stanciu Luminita A, Message Simon D, Edwards Michael R, Gern James E, Johnston Sebastian L
Department of Respiratory Medicine, National Heart and Lung Institute and Wright Fleming Institute of Infection and Immunity, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom.
J Virol. 2006 Aug;80(16):8248-58. doi: 10.1128/JVI.00162-06.
Rhinoviruses (RV) are the major cause of acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Rhinoviruses have been shown to activate macrophages, but rhinovirus replication in macrophages has not been reported. Tumor necrosis factor alpha (TNF-alpha) is implicated in the pathogenesis of acute exacerbations, but its cellular source and mechanisms of induction by virus infection are unclear. We hypothesized that rhinovirus replication in human macrophages causes activation and nuclear translocation of NF-kappaB, leading to TNF-alpha production. Using macrophages derived from the human monocytic cell line THP-1 and from primary human monocytes, we demonstrated that rhinovirus replication was productive in THP-1 macrophages, leading to release of infectious virus into supernatants, but was limited in monocyte-derived macrophages, likely due to type I interferon production, which was robust in monocyte-derived but deficient in THP-1-derived macrophages. Similar to bronchial epithelial cells, only small numbers of cells supported complete virus replication. We demonstrated RV-induced activation of NF-kappaB and colocalization of p65/NF-kappaB nuclear translocation with virus replication in both macrophage types. The infection induced TNF-alpha release in a time- and dose-dependent, RV serotype- and receptor-independent manner and was largely (THP-1 derived) or completely (monocyte derived) dependent upon virus replication. Finally, we established the requirement for NF-kappaB but not p38 mitogen-activated protein kinase in induction of TNF-alpha. These data suggest RV infection of macrophages may be an important source of proinflammatory cytokines implicated in the pathogenesis of exacerbations of asthma and COPD. They also confirm inhibition of NF-kappaB as a promising target for development of new therapeutic intervention strategies.
鼻病毒（RV）是哮喘和慢性阻塞性肺疾病（COPD）急性加重的主要原因。已证明鼻病毒可激活巨噬细胞，但尚未有鼻病毒在巨噬细胞中复制的报道。肿瘤坏死因子α（TNF-α）与急性加重的发病机制有关，但其细胞来源和病毒感染诱导机制尚不清楚。我们推测鼻病毒在人巨噬细胞中的复制会导致NF-κB的激活和核转位，从而导致TNF-α的产生。使用源自人单核细胞系THP-1和原代人单核细胞的巨噬细胞，我们证明鼻病毒在THP-1巨噬细胞中能有效复制，导致感染性病毒释放到上清液中，但在单核细胞衍生的巨噬细胞中复制受限，可能是由于I型干扰素的产生，其在单核细胞衍生的巨噬细胞中强烈表达，而在THP-1衍生的巨噬细胞中缺乏。与支气管上皮细胞类似，只有少数细胞支持完整的病毒复制。我们证明了RV诱导的NF-κB激活以及两种巨噬细胞类型中p65/NF-κB核转位与病毒复制的共定位。感染以时间和剂量依赖性、RV血清型和受体非依赖性方式诱导TNF-α释放，并且在很大程度上（THP-1衍生）或完全（单核细胞衍生）依赖于病毒复制。最后，我们确定了诱导TNF-α需要NF-κB而不是p38丝裂原活化蛋白激酶。这些数据表明巨噬细胞的RV感染可能是参与哮喘和COPD加重发病机制的促炎细胞因子的重要来源。它们还证实抑制NF-κB作为开发新治疗干预策略的有希望的靶点。
