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首页> 外文期刊>American Journal of Physiology >Fibrinogen binding to ICAM-1 promotes EGFR-dependent mucin production in human airway epithelial cells.
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Fibrinogen binding to ICAM-1 promotes EGFR-dependent mucin production in human airway epithelial cells.

机译：纤维蛋白原与ICAM-1的结合促进人气道上皮细胞中EGFR依赖性粘蛋白的产生。

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摘要

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)-alpha dose-dependently. 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-alpha. 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)-alpha/beta, and metalloproteases. These results suggest that fibrinogen binding to ICAM-1 promotes mucin production by decreasing TGF-alpha-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 PLC- and PKC-alpha/beta-dependent metalloprotease activation and subsequent metalloprotease-dependent EGFR reactivation.
机译：粘液分泌过多是慢性气道疾病（如哮喘，慢性阻塞性肺疾病（COPD）和囊性纤维化）的严重特征。尽管粘蛋白是通过激活EGF受体（EGFR）信号级联反应产生的，但在粘液分泌过多疾病中导致粘蛋白产生过度的机制尚不清楚。因为粘液分泌过多疾病患者的气道中ICAM-1和ICAM-1配体纤维蛋白原的表达增加，因此我们假设纤维蛋白原与ICAM-1的结合可以增加人气道中EGFR依赖性粘蛋白的产生（NCI-H292）上皮细胞。与此假设相符，我们发现，ICAM-1中和抗体和结合血纤蛋白原的ICAM-1（8-22）肽可剂量依赖性地降低由EGFR配体转化生长因子（TGF）-α诱导的粘蛋白生成。外源纤维蛋白原和与ICAM-1结合的纤维蛋白原（117-133）肽拯救了用ICAM-1（8-22）肽处理的细胞中的粘蛋白生成。出人意料的是，ICAM-1（8-22）肽增加了TGF-α处理的细胞中的EGFR磷酸酪氨酸和磷酸化ERK1 / 2。外源性纤维蛋白原，纤维蛋白原（117-133）肽和磷脂酶C（PLC）的选择性抑制剂可防止ICAM-1（8-22）肽诱导的EGFR磷酸酪氨酸和磷酸化ERK1 / 2的增加激酶C（PKC）-alpha / beta和金属蛋白酶。这些结果表明，与ICAM-1结合的纤维蛋白原通过降低TGF-α诱导的EGFR和ERK1 / 2激活而促进粘蛋白生成，而通过抑制早期的纤维蛋白原-ICAM-1依赖性降低EGFR和ERK1 / 2激活涉及PLC和PKC-α/β依赖性金属蛋白酶激活以及随后的金属蛋白酶依赖性EGFR再激活的正反馈途径。

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