Introduction

Bronchial asthma is characterized by chronic airway inflammation, leading to expiratory airflow limitation and presentation of respiratory symptoms (e.g., dyspnea and wheezing) (1). A small proportion of patients with asthma (5–10%) can be classified as having severe asthma, in which symptoms remain uncontrolled despite the administration of high-dose inhaled corticosteroids (i.e. fluticasone propionate) in combination with a second long-term controller medication (2). These patients represent a substantial economic burden owing to their symptoms, disease exacerbation, and medication-induced side effects, accounting for >60% of the medical costs associated with asthma (3). While eosinophilic asthma with persistent type-2 inflammation constitutes the most common phenotype of severe asthma, there is limited knowledge regarding the pathophysiology of refractory eosinophilic asthma.
Many reports have suggested that respiratory viral infections are associated with the onset and/or exacerbation of asthma. This is termed virus-induced asthma, and infection with a respiratory virus may be associated with >80% of asthma cases (4). Especially human rhinovirus (HRV), respiratory syncytial virus (RSV), and enteroviruses (EV) may cause virus-induced asthma (4-6). In general, the primary immune response against viruses is innate immunity (7, 8). Innate immunity in the host against RNA viruses reportedly involves various Toll-like receptors (TLR) including TLR3 and TLR4 (9), which are activated by viral RNA (7). Immune responses through the TLRs are associated with the pathophysiology of asthma, although the precise mechanisms are not fully understood.
Th2 cytokines, including interleukin (IL)-4 and IL-13, are closely related to various allergic diseases including asthma (10). Numerous reports have shown that IL-13 causes exacerbation of asthma (11-14). This cytokine is produced by Th2 lymphocytes, which act on the allergic immune cells (e.g., eosinophils and mast cells), inducing their migration from the vessel (15). Moreover, IL-13 can induce a chemokine, Chemokine (C-C motif) ligand 5 (CCL5), from various cells including airway epithelial cells (16, 17). CCL5 attracts T cells, its expression is regulated by activated T cells, and it has strong chemotactic activity for eosinophils (18). Thus IL-13 and CCL5 may be associated with asthma exacerbation, although this relationship remains unclear (10, 19, 20).
Furthermore, ruxolitinib, a Janus kinase (JAK) 1 and JAK2 subtype inhibitor, is used as a molecular targeted agent for the treatment of osteofibrosis (21, 22). TLR3, TLR4, and IL-13 may induce the phosphorylation of JAK1, resulting in allergic reactions. Thus, ruxolitinib may regulate the allergic reaction induced by TLRs and IL13 in the airway cells, leading to asthma remission.
Based on the available evidence, the objective of this study was to clarify the relationships among innate immunity induced by poly (I:C) (surrogate of RNA virus infection), allergic cytokine (IL-13), and chemokine (CCL5) in airway epithelial cells (BEAS-2B). We also examined whether ruxolitinib intervenes in these reactions.