Toll-like receptor 3 ligand specifically induced bronchial epithelial cell death in caspase dependent manner and functionally upregulated Fas expression

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. 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. 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. 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 virus-induced 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.