Viral infections of the airway can exacerbate
respiratory diseases, such as
asthma or
chronic obstructive pulmonary disease (
COPD), and accelerate
disease progression.
Phosphoinositide 3-kinase (PI3K)δ, a class 1A PI3K, has been studied as a potential target for achieving anti-oncogenic and anti-inflammatory effects. However, the role of PI3Kδ in
antiviral responses is poorly understood. Using a synthetic
double-stranded RNA poly I:C and a selective PI3Kδ inhibitor
IC87114, we investigated the role of PI3Kδ signaling in
poly I:C-induced expression of the T lymphocyte-inhibitory molecule programmed death 1
ligand 1 (PD-L1), inflammatory responses and
antiviral interferon (IFN) responses. C57BL/6N mice were treated with
IC87114 or vehicle by intratracheal (i.t.) instillation followed by i.t. administration of
poly I:C.
Poly I:C increased PD-L1 expression on epithelial cells, lymphocytes, macrophages, and neutrophils in the lungs and
IC87114 suppressed
poly I:C-induced PD-L1 expression on epithelial cells and neutrophils possibly via inhibition of the Akt/mTOR signaling pathway.
IC87114 also attenuated
poly I:C-induced increases in numbers of total cells, macrophages, neutrophils and lymphocytes, as well as levels of KC,
IL-6 and MIP-1β in bronchoalveolar lavage fluid. Gene expression of IFNβ, IFNλ2 and IFN-stimulated genes (ISGs) were upregulated in response to
poly I:C and a further increase in gene expression was observed following
IC87114 treatment. In addition,
IC87114 enhanced
poly I:C-induced phosphorylation of IRF3. We assessed the effects of
IC87114 on human primary bronchial epithelial cells (PBECs).
IC87114 decreased
poly I:C-induced PD-L1 expression on PBECs and secretion of
IL-6 and
IL-8 into culture supernatants.
IC87114 further enhanced
poly I:C- induced increases in the concentrations of IFNβ and IFNλ1/3 in culture supernatants as well as upregulated gene expression of ISGs in PBECs. Similar results were obtained in PBECs transfected with
siRNA targeting the PIK3CD gene encoding PI3K p110δ, and stimulated with
poly I:C. In human metapneumovirus (hMPV)
infection of PBECs,
IC87114 suppressed hMPV-induced PD-L1 expression and reduced viral replication without changing the production levels of IFNβ and IFNλ1/3 in culture supernatants. These data suggest that
IC87114 may promote virus elimination and clearance through PD-L1 downregulation and enhanced
antiviral IFN responses, preventing prolonged
lung inflammation, which exacerbates
asthma and
COPD.