Ruxolitinib inhibits poly (I:C) and IL-13-induced CCL5 production in
bronchial epithelial cells: A potential therapeutic agent for severe
Rationale Severe eosinophilic asthma is characterized by airway
eosinophilia and corticosteroid-resistance, commonly overlapping with
type-2 inflammation. It has been reported that CCL5 is involved in
asthma exacerbation due to RNA virus infections. We hypothesized that
treatment with a virus-associated ligand and a Th2-cytokine can
synergistically stimulate CCL5 production in bronchial epithelial cells.
We also aimed to evaluate the mechanisms underlying CCL5 production in
this in vitro model and to assess the potential of JAK1 as a novel
therapeutic target via the use of ruxolitinib. Methods We stimulated
primary normal human bronchial epithelial (NHBE) cells and BEAS-2B cells
with poly (I:C) along with IL-13 or IL-4, and assessed CCL5 production.
We also evaluated the signals involved in virus- and
Th2-cytokine-induced CCL5 production and explored a therapeutic agent
that attenuates the CCL5 production. Results Poly (I:C) stimulated NHBE
and BEAS-2B cells to produce CCL5. Poly (I:C) and IL-13 increased CCL5
production. Poly (I:C)-induced CCL5 production occurred via the
TLR3-IRF3 and IFNAR/JAK1-PI3K pathways, but not the IFNAR/JAK1-STATs
pathway. In addition, IL-13 did not augment poly (I:C)-induced CCL5
production via the canonical IL-13R/IL-4R/JAK1-STAT6 pathway but likely
via subsequent TLR3-IRF3-IFNAR/JAK1-PI3K pathways. JAK1 was identified
to be a potential therapeutic target for severe eosinophilic asthma. The
JAK1/2 inhibitor, ruxolitinib, was demonstrated to more effectively
decrease CCL5 production in BEAS-2B cells than fluticasone propionate.
Conclusion We have demonstrated that JAK1 is a possible therapeutic
target for severe corticosteroid-resistant asthma with airway
eosinophilia and persistent Th2-type inflammation, and that ruxolitinib
has potential as an alternative pharmacotherapy.