Airway smooth muscle cells (ASMCs) have been
reported to express Toll-like receptors (TLRs) and
take part in the pathogenesis of asthma
exacerbation. Though TLRs were found to activate
epidermal growth factor receptor (EGFR) in airway
epithelial cells, little is known about the
association of TLR ligands with EGFR signaling
pathways in ASMCs. Using primary cultured
ASMCs from Brown Norway rats, TLR4, eotaxin,
and RANTES mRNA were examined by real-time
quantitative RT-PCR after stimulation with the
TLR4 ligand, lipopolysaccharides (LPS). The
concentration of RANTES protein in culture
supernatant was measured by ELISA. The effect of
EGFR signaling inhibitors on RANTES expression
was examined as well. Phosphorylation of EGFR
after stimulation was examined by Western
Blotting. Rat ASMCs expressed TLR4 and eotaxin,
and LPS upregulated RANTES production. The
EGFR tyrosine kinase inhibitor AG1478, the
phosphoinositide 3-kinase (PI3K) inhibitor
LY294002, and the matrix metalloproteinase
(MMP) inhibitor GM6001 inhibited RANTES
expression induced by LPS. LPS phosphorylated
EGFR. TLR4 activation can induce RANTES
expression via EGFR transactivation and PI3K/Akt
pathway in rat ASMCs. MMP-induced EGFR
proligand cleavage and ligand binding to EGFR
seem to be involved in this pathway. These
findings may be critical in the pathogenesis of
asthma exacerbation by airway infection.
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