Involvement of toll-like receptor 2 and epidermal growth factor receptor signaling in epithelial expression of airway remodeling factors

Tetsuya Homma*, Atsushi Kato, Masafumi Sakashita, James E. Norton, Lydia A. Suh, Roderick G. Carter, Robert P. Schleimer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)471-481
Number of pages11
JournalAmerican journal of respiratory cell and molecular biology
Volume52
Issue number4
DOIs
StatePublished - Apr 1 2015

Keywords

  • Epidermal growth factor receptor
  • Matrix metalloproteinase 1
  • Remodeling; Toll-like receptor 2
  • Staphylococcus aureus

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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