Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
Airway Disease, National Heath and Lung Institute, Imperial College, London, UK.
Allergy. 2015 Aug;70(8):910-20. doi: 10.1111/all.12627. Epub 2015 Apr 24.
Asthma and other Th2 inflammatory conditions have been associated with increased susceptibility to viral infections. The mechanisms by which Th2 cytokines can influence immune responses to infections are largely unknown.
We measured the effects of Th2 cytokines (IL-4 and IL-13) on bronchial epithelial cell innate immune antiviral responses by assessing interferon (IFN-β and IFN-λ1) induction following rhinovirus (RV)-16 infection. We also investigated the modulatory effects of Th2 cytokines on Toll-like receptor 3 (TLR3), interferon-responsive factor 3 (IRF3) and nuclear factor (NF)-kB, that is key molecules and transcription factors involved in the rhinovirus-induced interferon production and inflammatory cascade. Pharmacological and redox modulation of these pathways was also assessed.
Th2 cytokines impaired RV-16-induced interferon production, increased rhinovirus replication and impaired TLR3 expression in bronchial epithelial cells. These results were replicated in vivo: we found increased IL-4 mRNA levels in nasal epithelial cells from nasal brushing of atopic rhinitis patients and a parallel reduction in TLR3 expression and increased RV-16 replication compared to nonatopic subjects. Mechanistically, Th2 cytokines impaired RV-16-induced activation of IRF3, but had no effects on RV-16-induced NF-kB activation in bronchial epithelial cell cultures. N-acetylcysteine and phosphoinositide 3-kinase (PI3K) inhibitor restored the inhibitory effects of Th2 cytokines over RV-16-induced activation of IRF3.
IL-4 and IL-13, through inhibition of TLR3 expression and signalling (IRF3), impair immune response to RV-16 infection. These data suggest that Th2 conditions increase susceptibility to infections and identify pharmacological approaches with potential to restore impaired immune response in these conditions.
哮喘和其他 Th2 炎症状态与病毒感染易感性增加有关。Th2 细胞因子影响感染免疫反应的机制在很大程度上尚不清楚。
我们通过评估鼻病毒（RV）-16 感染后干扰素（IFN-β 和 IFN-λ1）的诱导，来测量 Th2 细胞因子（IL-4 和 IL-13）对支气管上皮细胞先天抗病毒反应的影响。我们还研究了 Th2 细胞因子对 Toll 样受体 3（TLR3）、干扰素反应因子 3（IRF3）和核因子（NF）-kB 的调节作用，这些是涉及鼻病毒诱导干扰素产生和炎症级联的关键分子和转录因子。还评估了这些途径的药理和氧化还原调节。
Th2 细胞因子削弱了 RV-16 诱导的干扰素产生，增加了鼻病毒复制，并削弱了支气管上皮细胞中的 TLR3 表达。这些结果在体内得到了复制：我们发现，在特应性鼻炎患者的鼻拭子中，鼻上皮细胞中的 IL-4 mRNA 水平增加，而与非特应性患者相比，TLR3 表达降低，RV-16 复制增加。从机制上讲，Th2 细胞因子削弱了 RV-16 诱导的 IRF3 激活，但对支气管上皮细胞培养物中 RV-16 诱导的 NF-kB 激活没有影响。N-乙酰半胱氨酸和磷酸肌醇 3-激酶（PI3K）抑制剂恢复了 Th2 细胞因子对 RV-16 诱导的 IRF3 激活的抑制作用。
IL-4 和 IL-13 通过抑制 TLR3 表达和信号转导（IRF3），削弱了对 RV-16 感染的免疫反应。这些数据表明，Th2 状态增加了对感染的易感性，并确定了具有恢复这些状态下受损免疫反应潜力的药理方法。
