title: ADAM17 and EGFR regulate IL-6 receptor and amphiregulin mRNA expression and release in cigarette smoke-exposed primary bronchial epithelial cells from patients with chronic obstructive pulmonary disease (COPD).
abstract: Aberrant activity of a disintegrin and metalloprotease 17 (ADAM17), also known as TACE, and epidermal growth factor receptor (EGFR) has been suggested to contribute to chronic obstructive pulmonary disease (COPD) development and progression. The aim of this study was to investigate the role of these proteins in activation of primary bronchial epithelial cells differentiated at the air-liquid interface (ALI-PBEC) by whole cigarette smoke (CS), comparing cells from COPD patients with non-COPD CS exposure of ALI-PBEC enhanced ADAM17-mediated shedding of the IL-6 receptor (IL6R) and the EGFR agonist amphiregulin (AREG) toward the basolateral compartment, which was more pronounced in cells from COPD patients than in non-COPD controls. CS transiently increased IL6R and AREG mRNA in ALI-PBEC to a similar extent in cultures from both groups, suggesting that posttranslational events determine differential shedding between COPD and non-COPD cultures. We show for the first time by in situ proximity ligation (PLA) that CS strongly enhances interactions of phosphorylated ADAM17 with AREG and IL-6R in an intracellular compartment, suggesting that CS-induced intracellular trafficking events precede shedding to the extracellular compartment. Both EGFR and ADAM17 activity contribute to CS-induced IL-6R and AREG protein shedding and to mRNA expression, as demonstrated using selective inhibitors (AG1478 and TMI-2). Our data are consistent with an autocrine-positive feedback mechanism in which CS triggers shedding of EGFR agonists evoking EGFR activation, in ADAM17-dependent manner, and subsequently transduce paracrine signaling toward myeloid cells and connective tissue. Reducing ADAM17 and EGFR activity could therefore be a therapeutic approach for the tissue remodeling and inflammation observed in COPD.
authors: Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors: Marta
authors: M
authors: Stolarczyk
authors: Pulmonology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors: Gimano D
authors: GD
authors: Amatngalim
authors: Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors: Xiao
authors: X
authors: Yu
authors: Cell Biology, Erasmus MC, Rotterdam, The Netherlands.
authors: Mieke
authors: M
authors: Veltman
authors: Pulmonology, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors: Pieter S
authors: PS
authors: Hiemstra
authors: Cell Biology, Erasmus MC, Rotterdam, The Netherlands b.scholte@erasmusmc.nl.
authors: Bob J
authors: BJ
authors: Scholte
mesh_terms: D000072198:ADAM17 Protein / Q000235:genetics*; D000368:Aged; D056151:Airway Remodeling; D066258:Amphiregulin; D001980:Bronchi / Q000166:cytology*; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D019570:Inhalation Exposure; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000503:physiopathology; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics*; D019947:Receptors, Interleukin-6 / Q000378:metabolism*; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism*; D014026:Nicotiana / Q000009:adverse effects; D020032:Tyrphostins / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism
chemical_list: D066258:Amphiregulin; D011799:Quinazolines; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D020032:Tyrphostins; C101044:RTKI cpd; C512478:EGFR protein, human; D066246:ErbB Receptors; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: A disintegrin and metalloprotease 17 (ADAM17); Chronic Obstructive Pulmonary Disease (COPD); IL6 receptor (IL6R); TACE; amphiregulin (AREG); epidermal growth factor receptor (EGFR)