Open AccessADAM 17 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)
Author(s) -
Stolarczyk Marta,
Amatngalim Gimano D.,
Yu Xiao,
Veltman Mieke,
Hiemstra Pieter S.,
Scholte Bob J.
Publication year - 2016
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12878
Subject(s) - amphiregulin , autocrine signalling , paracrine signalling , cancer research , epidermal growth factor receptor , copd , medicine , endocrinology , immunology , receptor
Aberrant activity of a disintegrin and metalloprotease 17 ( ADAM 17), 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 ADAM 17‐mediated shedding of the IL ‐6 receptor ( IL 6R) 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 IL 6R 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 ADAM 17 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 ADAM 17 activity contribute to CS ‐induced IL ‐6R and AREG protein shedding and to mRNA expression, as demonstrated using selective inhibitors ( AG 1478 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 ADAM 17‐dependent manner, and subsequently transduce paracrine signaling toward myeloid cells and connective tissue. Reducing ADAM 17 and EGFR activity could therefore be a therapeutic approach for the tissue remodeling and inflammation observed in COPD.