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Autocrine effect of EGFR ligands on the pro-inflammatory response induced by PM2.5 exposure in human bronchial epithelial cells

Archives of Toxicology volume 86, pages 1537–1546 (2012)Cite this article

Abstract

Human exposure to PM2.5 (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 PM2.5, 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 PM2.5-induced GM-CSF release. PM2.5 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 PM2.5 demonstrates that PM2.5-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 PM2.5-induced GM-CSF release as well as the silencing of TACE by siRNA. We provide evidence that the pro-inflammatory response induced by PM2.5 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.

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Acknowledgments

The authors thank Annie Jaeger for her excellent technical help in cell culture (RMCX). This work was founded by grants from ADEME-Primequal (no. 0462C0056), Legs Poix, the Caisse d’Assurance Maladie des Professions Libérales de Province (Paris, France). K.R. was funded by ADEME and M.R. by the “ABIES” PhD programme for their PhD grants.

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The authors declare that they have no conflict of interest.

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Affiliations

  1. 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, Rodolphe Hamel, Mélina Rumelhard & Francelyne Marano

  2. Laboratory of Molecular and Cellular Responses to Xenobiotics, Unit of Functional and Adaptive Biology (BFA) EAC CNRS 4413, Paris Diderot University, Sorbonne Paris Cité, 5 rue Thomas Mann, case 7073, 75 205, Paris cédex 13, France

    Armelle Baeza-Squiban

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  1. Kiran Ramgolam
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  2. Rodolphe Hamel
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  3. Mélina Rumelhard
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  4. Francelyne Marano
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  5. Armelle Baeza-Squiban
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Correspondence to Armelle Baeza-Squiban.

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Ramgolam, K., Hamel, R., Rumelhard, M. et al. Autocrine effect of EGFR ligands on the pro-inflammatory response induced by PM2.5 exposure in human bronchial epithelial cells. Arch Toxicol 86, 1537–1546 (2012). https://doi.org/10.1007/s00204-012-0863-x

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  • DOI: https://doi.org/10.1007/s00204-012-0863-x

Keywords

  • Fine particles
  • Amphiregulin
  • Airway
  • TACE
  • 16HBE
  • Inflammation