Yoshizumi Masakazu, Kimura Hirokazu, Okayama Yoshimichi, Nishina Atsuyoshi, Noda Masahiro, Tsukagoshi Hiroyuki, Kozawa Kunihisa, Kurabayashi Masahiko
Gunma Prefectural Institute of Public Health and Environmental Sciences Maebashi-shi, Gunma, Japan.
Front Microbiol. 2010 Nov 15;1:124. doi: 10.3389/fmicb.2010.00124. eCollection 2010.
Respiratory viruses such as parainfluenza virus (PIV) in individuals with certain genetic predispositions in early life are associated with the induction of wheezing, which can progress to the development of asthma. It has been suggested that aberrant production of various cytokines due to viral infection are associated with virus-induced asthma. However, the mechanisms of how respiratory viruses induce and exacerbate asthma have yet to be clarified. To examine cytokine responses to PIV infection, we assessed 27 cytokine levels released from PIV-infected human fetal lung fibroblasts. In addition, we examined relationships between these cytokine responses and signaling pathways (IκB kinase and p38 MAPK) in PIV-infected cells. At 24 h after infection, PIV-infected cells significantly released a number of cytokines, namely, proinflammatory cytokines [interleukins (IL)-1β, IL-6, and tumor necrosis factor-α], anti-inflammatory cytokine (IL-1ra), Th1 cytokines (interferon-γ, and IL-2), Th2 cytokines (IL-4, IL-5, and IL-10), granulopoiesis-inducing cytokines (granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor), neutrophil recruitment-inducing cytokines (IL-8 and interferon-inducible protein-10), and eosinophil recruitment-inducing cytokines (eotaxin and regulated on activation normal T-cell expressed and secreted). PIV infection enhanced phosphorylation of both IκB and p38 MAPK, but not Akt, in the cells. Signaling pathway inhibitors, BMS-345541 (a specific IκB kinase inhibitor) and SB203580 (a specific p38 MAPK inhibitor), significantly suppressed release of these cytokines from PIV-infected cells. The results indicate that PIV infection induces aberrant production and release of various cytokines through IκB kinase and p38 MAPK pathways in human lung fibroblasts. Overproduction and imbalance of these cytokines may be partially associated with the pathophysiology of virus-induced asthma.
在生命早期具有某些遗传易感性的个体中，呼吸道病毒如副流感病毒（PIV）与喘息的诱发有关，喘息可能会发展为哮喘。有人提出，病毒感染导致的各种细胞因子异常产生与病毒诱导的哮喘有关。然而，呼吸道病毒如何诱发和加重哮喘的机制尚待阐明。为了研究对PIV感染的细胞因子反应，我们评估了PIV感染的人胎儿肺成纤维细胞释放的27种细胞因子水平。此外，我们研究了这些细胞因子反应与PIV感染细胞中的信号通路（IκB激酶和p38丝裂原活化蛋白激酶）之间的关系。感染后24小时，PIV感染的细胞显著释放多种细胞因子，即促炎细胞因子[白细胞介素（IL）-1β、IL-6和肿瘤坏死因子-α]、抗炎细胞因子（IL-1ra）、Th1细胞因子（干扰素-γ和IL-2）、Th2细胞因子（IL-4、IL-5和IL-10）、粒细胞生成诱导细胞因子（粒细胞集落刺激因子和粒细胞-巨噬细胞集落刺激因子）、中性粒细胞募集诱导细胞因子（IL-8和干扰素诱导蛋白10）以及嗜酸性粒细胞募集诱导细胞因子（嗜酸性粒细胞趋化因子和活化正常T细胞表达和分泌的调控因子）。PIV感染增强了细胞中IκB和p38丝裂原活化蛋白激酶的磷酸化，但未增强Akt的磷酸化。信号通路抑制剂BMS-345541（一种特异性IκB激酶抑制剂）和SB203580（一种特异性p38丝裂原活化蛋白激酶抑制剂）显著抑制了这些细胞因子从PIV感染细胞中的释放。结果表明，PIV感染通过人肺成纤维细胞中的IκB激酶和p38丝裂原活化蛋白激酶途径诱导各种细胞因子的异常产生和释放。这些细胞因子的过度产生和失衡可能部分与病毒诱导哮喘的病理生理学有关。
