Bronchial epithelial compression regulates epidermal growth factor receptor family ligand expression in an autocrine manner.
The epidermal growth factor receptor (EGFR), an important signaling pathway in airway biology, is stimulated by compressive stress applied to human airway epithelial cells. Although the EGFR ligand, heparin-binding epidermal growth factor-like growth factor (HB-EGF), is known to be released as a result of this stimulation, whether compressive stress enhances expression of other EGFR ligands, and the duration of mechanical compression required to initiate this response, is not known. Human airway epithelial cells were exposed to compressive stress, and expression of four EGFR ligands was examined by quantitative PCR. Cells were exposed to: (1) continuous compressive stress over 8 h, (2) compression with and without EGFR inhibitor (AG1478), or (3) time-limited compression (3.75, 7.5, 15, 30, and 60 min). Compressive stress produced a sustained upregulation of the EGFR ligands HB-EGF, epiregulin, and amphiregulin, but not transforming growth factor-alpha. Inhibition with AG1478 demonstrated that expression of HB-EGF, epiregulin, and amphiregulin is dependent on the signaling via the EGFR. Immunostaining for epiregulin protein demonstrated increased expression with compression and attenuation with EGFR inhibition. The response of all three EGFR ligands persisted long after the mechanical stimulus was removed. Taken together, these data suggest the possibility of a mechanically activated EGFR autocrine feedback loop involving selected EGFR ligands.
Chu
Eric K
EK
Department of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. echu@partners.org
Foley
John S
JS
Cheng
Jason
J
Patel
Anita S
AS
Drazen
Jeffrey M
JM
Tschumperlin
Daniel J
DJ
D066258:Amphiregulin; D019898:Autocrine Communication / Q000502:physiology*; D001980:Bronchi / Q000033:anatomy & histology* / Q000378:metabolism; D002478:Cells, Cultured; D019245:Compressive Strength; D066255:EGF Family of Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066260:Epiregulin; D066246:ErbB Receptors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D011799:Quinazolines; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D013997:Time Factors; D020032:Tyrphostins / Q000494:pharmacology
C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; C587880:EREG protein, human; D004791:Enzyme Inhibitors; D066260:Epiregulin; D006023:Glycoproteins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D004815:Epidermal Growth Factor; D066246:ErbB Receptors