Fibrinogen binding to ICAM-1 promotes EGFR-dependent mucin production in human airway epithelial cells

Abstract

Kim S, Nadel JA. Fibrinogen binding to ICAM-1 promotes EGFR-dependent mucin production in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 297: L174 -L183, 2009. First published May 8, 2009 doi:10.1152/ajplung.00032.2009.-Mucous hypersecretion is a serious feature of chronic airway diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. Although mucins are produced via activation of an EGF receptor (EGFR) signaling cascade, the mechanisms leading to exaggerated mucin production in mucous hypersecretory diseases are unknown. Because expression of ICAM-1 and of the ICAM-1 ligand fibrinogen is increased in the airways of subjects with mucous hypersecretory diseases, we hypothesized that fibrinogen binding to ICAM-1 could increase EGFR-dependent mucin production in human airway (NCI-H292) epithelial cells. Consistent with this hypothesis, we found that an ICAM-1 neutralizing antibody and an ICAM-1(8 -22) peptide that binds fibrinogen decreased mucin production induced by the EGFR ligand transforming growth factor (TGF)-␣ dosedependently. Exogenous fibrinogen and a fibrinogen(117-133) peptide that binds ICAM-1 rescued mucin production in cells treated with the ICAM-1(8 -22) peptide. Surprisingly, the ICAM-1(8 -22) peptide increased EGFR phosphotyrosine and phospho-ERK1/2 in cells treated with TGF-␣. The ICAM-1(8 -22) peptide-induced increases in EGFR phosphotyrosine and phospho-ERK1/2 were prevented by exogenous fibrinogen, by the fibrinogen(117-133) peptide, and by selective inhibitors of phospholipase C (PLC), protein kinase C (PKC)-␣/␤, and metalloproteases. These results suggest that fibrinogen binding to ICAM-1 promotes mucin production by decreasing TGF-␣-induced EGFR and ERK1/2 activation and that the fibrinogen-ICAM-1-dependent decrease in EGFR and ERK1/2 activation occurs via inhibition of an early positive feedback pathway involving PLCand PKC-␣/␤-dependent metalloprotease activation and subsequent metalloprotease-dependent EGFR reactivation.

Fibrinogen β–derived Bβ15-42 peptide protects against kidney ischemia/ reperfusion injury

“…15 Fg has been shown to have multiple binding partners, such as ␤3-integrin 45 and ICAM-1, 46 regulating the tissue repair process in neurons and lung epithelial cells. 47 Given that both ␤3-integrin and ICAM-1 expression on renal epithelial cells increases after kidney injury, [48][49][50] it remains to be investigated whether Fg or the B␤ peptide aids in renal epithelial proliferation and extracellular remodeling via one of the known ligands and pathways. Kidney regeneration, after an episode of AKI, is a major determinant of outcome for patients with AKI and therefore the use of B␤ peptide offers a novel therapy to improve the rate or effectiveness of the tissue repair process after ischemic kidney damage.…”

CCL20/CCR6 Feedback Exaggerates Epidermal Growth Factor Receptor-Dependent MUC5AC Mucin Production in Human Airway Epithelial (NCI-H292) Cells

“…NCI-H292 and NHBE cell lysates were prepared, and immunoblotting was performed as described previously (34). In brief, equal amounts of protein were separated by SDS-(7.5%) PAGE, transferred to polyvinylidene difluoride membranes (Bio-Rad, Hercules, CA), and blotted with mAbs against either human CCR6 (R&D Systems) or human EGFR (R&D Systems).…”

Epidermal growth factor receptor reactivation induced by E-prostanoid-3 receptor- and tumor necrosis factor-alpha-converting enzyme-dependent feedback exaggerates interleukin-8 production in airway cancer (NCI-H292) cells

“…Human lung adenocarcinoma (NCI-H292) cells were purchased from American Type Culture Collection (Manassas, VA) and grown in RPMI 1640 medium containing 10% fetal bovine serum, penicillin (100 U/ml), streptomycin (100 μg/ml), and 25 mM HEPES at 37°C in a humidified 5% CO 2 water-jacketed incubator as described previously [24]. The NCI-H292 cell line was derived from a lymph node metastasis of a pulmonary mucoepidermoid carcinoma.…”

“…Immunoblotting NCI-H292 and NHBE cell lysates were prepared and immunoblotting was performed as described previously [24]. In brief, equal amounts of protein were separated by SDS-(7.5%)PAGE, transferred to polyvinylidene difluoride membranes (Biorad, Hercules, CA), and blotted with mouse monoclonal antibodies against human EGFR (R&D Systems) or human TACE (Santa Cruz Biotechnology, Santa Cruz, CA), or blotted with rabbit polyclonal antibodies against human COX-2 (Santa Cruz Biotechnology), human EP1-4 receptors (Cayman Chemical), or human beta-actin (Santa Cruz Biotechnology).…”