PT  - JOURNAL ARTICLE
AU  - J. Øvrevik
AU  - M. Refsnes
AU  - A.I. Totlandsdal
AU  - J.A. Holme
AU  - P.E. Schwarze
AU  - M. Låg
TI  - TACE/TGF-α/EGFR regulates CXCL8 in bronchial epithelial cells exposed to particulate matter components
AID  - 10.1183/09031936.00171110
DP  - 2011 Nov 01
TA  - European Respiratory Journal
PG  - 1189--1199
VI  - 38
IP  - 5
4099  - http://erj.ersjournals.com/content/38/5/1189.short
4100  - http://erj.ersjournals.com/content/38/5/1189.full
SO  - Eur Respir J2011 Nov 01; 38
AB  - Airborne particulate matter (PM) may induce or exacerbate neutrophilic airway disease by triggering the release of inflammatory mediators, such as CXC chemokine ligand (CXCL)8, from the airway epithelium. It is still unclear which PM components are driving CXCL8 responses, as most candidates occur at low concentrations in the dusts. We therefore hypothesised that different PM constituents may contribute through common mechanisms to induce CXCL8. Human bronchial epithelial cells (BEAS-2B) were exposed to different PM components (Zn2+/Fe2+ salts, 1-nitropyrene, lipopolysaccharide and diesel exhaust/mineral particles). Gene expression patterns were detected by real-time PCR array. CXCL8 responses were measured by real-time PCR and ELISA. CXCL8 regulation was assessed with a broad inhibitor panel and neutralising antibodies. Epidermal growth factor receptor (EGFR) phosphorylation was examined by immunoprecipitation and Western blotting. Component-induced gene expression was mainly linked to nuclear factor-κB, Ca2+/protein kinase C, phospholipase C, low-density lipoprotein and mitogenic signalling. Many inhibitors attenuated CXCL8 release induced by all PM components, but to varying extents. However, EGFR inhibition strongly reduced CXCL8 release induced by all test compounds and selected compounds increased EGFR phosphorylation. Interference with transforming growth factor (TGF)-α or tumour necrosis factor-α-converting enzyme (TACE), which mediates TGF-α ectodomain shedding, also attenuated CXCL8 release. Different PM constituents induced CXCL8 partly through similar signalling pathways but the relative importance of the different pathways varied. However, TACE/TGF-α/EGFR signalling appears to be a convergent pathway regulating innate immune responses of airway epithelial cells upon exposure to multiple airborne pollutants.