title: Autocrine effect of EGFR ligands on the pro-inflammatory response induced by PM(2.5) exposure in human bronchial epithelial cells.
abstract: Human exposure to PM(2.5) (particulate matter with an aerodynamic diameter below 2.5 μm) is known to be responsible for airway inflammation and may also induce airway remodelling. In respiratory epithelial cells exposed to PM(2.5), releases of pro-inflammatory cytokines such as granulocyte macrophage-colony stimulating factor (GM-CSF) and growth factor ligands of the epidermal growth factor receptor (EGFR) are increased. The present study aimed at determining the involvement of EGFR ligands by autocrine effects in PM(2.5)-induced GM-CSF release. PM(2.5) exposure triggers GM-CSF release by human bronchial epithelial (HBE) cells. This release is dependent on EGFR activation by ligand binding as it is inhibited by AG1478, an inhibitor of EGFR tyrosine kinase activity as well as by a neutralizing anti-EGFR antibody. The use of conditioned medium from cells previously exposed to PM(2.5) demonstrates that PM(2.5)-exposed cells release soluble EGFR ligands able to induce GM-CSF release by an autocrine manner. It was further demonstrated by inhibiting tumour-necrosis factor-alpha converting enzyme (TACE) that is involved in some EGFR ligand shedding. TAPI-2 and GM-6001, two TACE inhibitors, prevented the PM(2.5)-induced GM-CSF release as well as the silencing of TACE by siRNA. We provide evidence that the pro-inflammatory response induced by PM(2.5) exposure on HBE cells, results from an autocrine effect of EGFR ligands released by TACE activity. This autocrine loop by eliciting and sustaining inflammation could contribute to exacerbation of airway remodelling in respiratory-compromised individuals.
authors.affiliation: Laboratory of Molecular and Cellular Responses to Xenobiotics, Unit of Functional and Adaptive Biology (BFA) EAC CNRS 4413, Paris Diderot University, Sorbonne Paris Cité, 75 013 Paris, France. kiran_ramgolam@hotmail.com
authors.forename: Kiran
authors.initials: K
authors.lastname: Ramgolam
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Hamel
authors.forename: Mélina
authors.initials: M
authors.lastname: Rumelhard
authors.forename: Francelyne
authors.initials: F
authors.lastname: Marano
authors.forename: Armelle
authors.initials: A
authors.lastname: Baeza-Squiban
mesh_terms: D051722:ADAM Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D056151:Airway Remodeling / Q000187:drug effects; D019898:Autocrine Communication / Q000187:drug effects; D001980:Bronchi / Q000166:cytology / Q000187:drug effects; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism; D020868:Gene Silencing; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology; D010316:Particle Size; D052638:Particulate Matter / Q000633:toxicity*; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D052638:Particulate Matter; D011799:Quinazolines; D034741:RNA, Small Interfering; D020032:Tyrphostins; C101044:RTKI cpd; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human