Abstract
Background: Viral infections are the most common cause of asthma exacerbation. Virally infected
epithelial cells undergo apoptosis. Although in healthy conditions, apoptosis may have a host-defensive
role in limiting virus spread, this process may have a detrimental effect on damaged epithelium in
asthma. Toll-like receptors (TLRs) are the receptors for various pathogens, and viruses possess several
components that can activate TLR3, TLR4, and TLR7/8. However, as it has not been determined as to
which component is responsible for virus-induced epithelial cell apoptosis, we comprehensively
analyzed the effects of all TLR ligands on apoptosis.
Methods: BEAS-2B cells or primary cultured human bronchial epithelial cells (PBECs) were stimulated by
TLR 2, 3, 4, 5, 7/8, and 9 ligands and cell death was analyzed by flow cytometry. Chemokine generations
induced by these ligands were also analyzed.
Results: The TLR3 ligand polyinosinic-polycytidylic acid (poly I:C) specifically induced chemokine
generation and apoptosis, while other TLR ligands including those for TLR5, 7/8, and 9 had no effect. The
response to poly I:C had two phases, which included rapid secretion of chemokines and subsequent
apoptosis in a later phase. Poly I:C induced apoptosis in a caspase-dependent manner and functionally
upregulated the expression of Fas.
Conclusions: Previous findings indicating that viruses induced caspase-dependent death and upregulated
Fas expression were reproduced by poly I:C, suggesting the central role of dsRNA/TLR3 in virusinduced
apoptosis. Since these processes may have detrimental effects on pre-existing epithelial damage,
the dsRNA/TLR3 pathway may be potential novel treatment target for virus-induced exacerbation of
asthma.
