Abstract
Impaired interferon (IFN) production has been observed in various obstructive respiratory diseases. This contributes to enhanced sensitivity towards viral infections triggering acute exacerbations. To compensate for this impaired host IFN response, there is need to explore new therapeutic strategies, like exogenous administration of IFNs as prophylactic treatment. In the present study, we examined the protective potential of IFN-λ1 and compared it with the previously established protecting effect of IFN-β. A549 cells and human primary bronchial epithelial cells were first treated with either IFN-β (500 IU/ml) or IFN-λ1 (500 ng/ml) for 18 h. For infection, two approaches were adopted: i) Continuous scenario: after pre-treatment, cells were infected immediately for 24 h with human rhinovirus 1B (HRV1B) in IFN-containing medium, or were cultured for another 72 h in IFN-containing medium, and then infected for 24 h with HRV1B, ii) Pre-treatment scenario: IFN-containing medium was replaced after 18 h and cells were infected for 4 h either immediately after pre-treatment or after additional culturing for 72 h in IFN-free medium. The protective effect was evaluated in terms of reduction in the number of viral copies/infectious progeny, and enhanced expression of IFN-stimulated genes (ISGs). In both cell types and in both approaches, IFN-λ1 and IFN-β treatment resulted in pronounced and long-lasting antiviral effects exemplified by significantly reduced viral copy numbers and diminished infectious progeny. This was associated with strong up-regulation of multiple ISGs. However, in contrast to the IFN-β induced expression of ISGs, which decreased over time, expression of ISGs induced by IFN-λ1 was sustained or even increased over time. Here we demonstrate that the protective potential of IFN-λ1 is comparable to IFN-β. Yet, the long-lasting induction of ISGs by IFN-λ1 and most likely less incitement of side effects due to more localized expression of its receptors could make it an even more promising candidate for prophylactic treatment than IFN-β.
Highlights
Acute exacerbations are the major cause of morbidity and mortality in chronic respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD)
IFN-l1 Induces Strong Antiviral State in A549 Cells In our previous study we have shown that exogenous administration of IFN-b induced a strong up-regulation of ISGs in respiratory epithelial cells [22]
To put our results with A549 cells into perspective, we repeated some of the experiments with Primary bronchial epithelial cells (PBECs). First we infected these cells with HRV1B for either 4 or 24 h and in line with our results found in A549 cells, we were unable to detect an up-regulation of IFN-b, IFN-l1 or any of the ISGs
Summary
Acute exacerbations are the major cause of morbidity and mortality in chronic respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD). They increase the economic burden because of extra healthcare, which has to be provided to the patients [1,2]. In response to viral infections, airway epithelial cells become activated and start producing different antiviral mediators and pro-inflammatory cytokines. These mediators and cytokines combat invading viruses, and recruit and activate other immune cells and initiate mechanisms of adaptive immunity [9,10]. Type-III IFNs are considered to be more important for mucosal antiviral defense, while type-I IFNs might be more important for clearance of systemic viral infections [15,16]
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