Autocrine ligands for the epidermal growth factor receptor mediate interleukin-8 release from bronchial epithelial cells in response to cigarette smoke

Am J Respir Cell Mol Biol. 2002 Jul;27(1):85-90. doi: 10.1165/ajrcmb.27.1.4789.


Airway neutrophilia is a prominent feature of chronic obstructive pulmonary disease. As cigarette smoke (CS) and epidermal growth factor (EGF) both cause release of interleukin-8 (IL-8) from epithelial cells in vitro, we investigated whether autocrine ligands for the EGF receptor (EGFR) are involved in this proinflammatory response to CS. NCI-H292 or primary bronchial epithelial cells were cultured with or without cigarette smoke extract (CSE) or EGF for 6-48 h. We then tested culture supernatants for lactate dehydrogenase activity to assess cell viability, and for IL-8 and EGFR ligands by ELISA; quantitative RT-PCR was used to measure IL-8 and EGFR ligand mRNA. EGF and low concentrations of CSE both promoted cell survival and caused enhanced transcription and release of IL-8. Similarly, levels of mRNA encoding transforming growth factor alpha (TGF-alpha), heparin-binding EGF-like growth factor, and amphiregulin (AR) were increased, as was shedding of TGF-alpha and AR protein into the culture medium. With the exception of AR gene transcription, the CS-induced responses were blocked by the EGFR-selective kinase inhibitor AG1478. Furthermore, ~ 45% of CS-induced IL-8 release was inhibited by a neutralising anti-EGFR. Our data indicate that secretion of IL-8 in response to CSE is dependent on EGFR activation and that autocrine production of TGF-alpha makes a substantial contribution to this response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amphiregulin
  • Bronchi / cytology
  • Bronchi / metabolism
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • EGF Family of Proteins
  • Epidermal Growth Factor / genetics
  • Epidermal Growth Factor / metabolism*
  • ErbB Receptors / metabolism*
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Growth Substances / genetics
  • Growth Substances / metabolism
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Intercellular Signaling Peptides and Proteins*
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism*
  • Middle Aged
  • Respiratory Mucosa / metabolism*
  • Smoking / metabolism*
  • Tobacco / adverse effects
  • Transforming Growth Factor alpha / genetics
  • Transforming Growth Factor alpha / metabolism*
  • Tumor Cells, Cultured


  • AREG protein, human
  • Amphiregulin
  • EGF Family of Proteins
  • Glycoproteins
  • Growth Substances
  • HBEGF protein, human
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-8
  • Transforming Growth Factor alpha
  • Epidermal Growth Factor
  • ErbB Receptors