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.