Autocrine ligands of the epithelial growth factor receptor mediate inflammatory responses to diesel exhaust particles

Respiratory Research

Donna E Davies²  Anthony J Frew¹  Stephen T Holgate¹  Sarah M Puddicombe¹  Lynnsey M Hamilton¹  Sam Parnia¹ 

[1] The Brooke Laboratories, Division of Infection, Inflammation and Repair, School of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK;Allergy & Inflammation Research, The Brooke Laboratory, Level F South Block, Mailpoint 888, Southampton General Hospital, Southampton SO16 6YD, UK

关键词: Ligand shedding;    Transactivation;    Interleukin-8;    Epidermal growth factor receptor;    Inflammation;    Neutrophilia;    Air pollution;   

Others  :  790396
DOI  :  10.1186/1465-9921-15-22

 received in 2013-05-24, accepted in 2014-02-03,  发布年份 2014

【 摘 要 】

Background

Diesel exhaust is associated with cardiovascular and respiratory mortality and morbidity. Acute exposure leads to increased IL-8 expression and airway neutrophilia, however the mechanism of this response is unknown. Objectives: As cigarette smoke-induced IL-8 expression by epithelial cells involves transactivation of the epidermal growth factor receptor (EGFR), we studied the effects of diesel exhaust particles (DEP) on IL-8 release and the role of the EGFR.

Methods

Primary bronchial epithelial cells (PBEC) were exposed to DEPs or carbon black. IL-8 and EGFR ligand expression (transforming growth factor alpha (TGFα), heparin-binding EGF-like growth factor, and amphiregulin (AR)) were assessed by quantitative RT-PCR and ELISA.

Results

DEP, but not carbon black, caused a dose-dependent increase in mitogen-activated protein kinase (MAPK) activation and IL-8 expression, however above 50 μg/ml there was an increase in cytotoxicity. At 50 μg/ml, DEPs stimulated transcription and release of IL-8 and EGFR ligands. IL-8 release was blocked by EGFR neutralizing antibodies, an EGFR-selective tyrosine kinase inhibitor and by the metalloprotease inhibitor, GM6001, which blocks EGFR ligand shedding. Neutralizing antibodies to AR, TGFα and heparin-binding (HB)-EGF reduced DEP-induced IL-8 by >50%. Conclusion Expression of IL-8 in response to DEPs is dependent on EGFR activation and that autocrine production of EGFR ligands makes a substantial contribution to this response. Capsule Summary: This study identifies a mechanism whereby diesel particles stimulates IL-8 release from bronchial epithelial cells. This mechanism may help to explain the recruitment of neutrophils into the airways of people exposed to particulate air pollution.

【 授权许可】

   
2014 Parnia et al.; licensee BioMed Central Ltd.

【 图 表 】

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