TY - JOUR
T1 - Involvement of toll-like receptor 2 and epidermal growth factor receptor signaling in epithelial expression of airway remodeling factors
AU - Homma, Tetsuya
AU - Kato, Atsushi
AU - Sakashita, Masafumi
AU - Norton, James E.
AU - Suh, Lydia A.
AU - Carter, Roderick G.
AU - Schleimer, Robert P.
N1 - Publisher Copyright:
© 2015 by the American Thoracic Society.
Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - Staphylococcus aureus (SA) colonization and infection is common, and may promote allergic or inflammatory airway diseases, such as asthma, cystic fibrosis, and chronic rhinosinusitis by interacting with airway epithelial cells. Airway epithelial cells not only comprise a physical barrier, but also play key roles in immune, inflammatory, repair, and remodeling responses upon encounters with pathogens. To elucidate the impact of SA on epithelial-mediated remodeling of allergic airways, we tested the hypothesis that SA can enhance the remodeling process. Normal human bronchial epithelial (NHBE) cells were stimulated with heat-killed SA (HKSA) or transforming growth factor (TGF) a. Cell extracts were collected to measure mRNA (real-time RT-PCR) and signaling molecules (Western blot); supernatants were collected to measure protein (ELISA) after 24 hours of stimulation. Epidermal growth factor receptor (EGFR) signaling inhibition experiments were performed using a specific EGFR kinase inhibitor (AG1478) and TGF-a was blocked with an anti-TGF-a antibody. HKSA induced both mRNA and protein for TGF-a and matrix metalloproteinase (MMP) 1 from NHBE cells by a Toll-like receptor 2-dependent mechanism. Recombinant human TGF-a also induced mRNA and protein for MMP-1 from NHBE cells; anti-TGF-a antibody inhibited HKSA-induced MMP-1, suggesting that endogenous TGF-a mediates the MMP-1 induction by HKSA. HKSA-induced MMP-1 expression was suppressed when a specific EGFR kinase inhibitor was added, suggesting that EGFR signaling was mediating the HKSA-induced MMP-1 release. Exposure or colonization by SA in the airway may enhance the remodeling of tissue through a TGF-a-dependent induction of MMP-1 expression, and may thereby promote remodeling in airway diseases in which SA is implicated, such as asthma and chronic rhinosinusitis.
AB - Staphylococcus aureus (SA) colonization and infection is common, and may promote allergic or inflammatory airway diseases, such as asthma, cystic fibrosis, and chronic rhinosinusitis by interacting with airway epithelial cells. Airway epithelial cells not only comprise a physical barrier, but also play key roles in immune, inflammatory, repair, and remodeling responses upon encounters with pathogens. To elucidate the impact of SA on epithelial-mediated remodeling of allergic airways, we tested the hypothesis that SA can enhance the remodeling process. Normal human bronchial epithelial (NHBE) cells were stimulated with heat-killed SA (HKSA) or transforming growth factor (TGF) a. Cell extracts were collected to measure mRNA (real-time RT-PCR) and signaling molecules (Western blot); supernatants were collected to measure protein (ELISA) after 24 hours of stimulation. Epidermal growth factor receptor (EGFR) signaling inhibition experiments were performed using a specific EGFR kinase inhibitor (AG1478) and TGF-a was blocked with an anti-TGF-a antibody. HKSA induced both mRNA and protein for TGF-a and matrix metalloproteinase (MMP) 1 from NHBE cells by a Toll-like receptor 2-dependent mechanism. Recombinant human TGF-a also induced mRNA and protein for MMP-1 from NHBE cells; anti-TGF-a antibody inhibited HKSA-induced MMP-1, suggesting that endogenous TGF-a mediates the MMP-1 induction by HKSA. HKSA-induced MMP-1 expression was suppressed when a specific EGFR kinase inhibitor was added, suggesting that EGFR signaling was mediating the HKSA-induced MMP-1 release. Exposure or colonization by SA in the airway may enhance the remodeling of tissue through a TGF-a-dependent induction of MMP-1 expression, and may thereby promote remodeling in airway diseases in which SA is implicated, such as asthma and chronic rhinosinusitis.
KW - Epidermal growth factor receptor
KW - Matrix metalloproteinase 1
KW - Remodeling; Toll-like receptor 2
KW - Staphylococcus aureus
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U2 - 10.1165/rcmb.2014-0240OC
DO - 10.1165/rcmb.2014-0240OC
M3 - Article
C2 - 25180535
AN - SCOPUS:84929657919
VL - 52
SP - 471
EP - 481
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 4
ER -