Acidic mammalian chitinase is secreted via an ADAM17/epidermal growth factor receptor-dependent pathway and stimulates chemokine production by pulmonary epithelial cells.
Acidic mammalian chitinase (AMCase) is expressed in an exaggerated fashion in epithelial cells at sites of pulmonary T helper cell type 2 inflammation and plays important roles in the pathogenesis of anti-parasite and asthma-like responses. However, the mechanisms that control epithelial cell AMCase secretion and its effector responses have not been adequately defined. To address these issues, we used in vivo and in vitro experimental systems to define the pathways of epithelial AMCase secretion and its epithelial regulatory effects. Here we demonstrate that, in murine T helper cell type 2 modeling systems, AMCase colocalizes with the epidermal growth factor receptor (EGFR) and ADAM17 (a membrane disintegrin and metallopeptidase 17) in lung epithelial cells. In vitro cotransfection experiments in A549 cells demonstrated that AMCase and EGFR physically interact with each other. Cotransfection of AMCase and EGFR also increased, whereas EGFR inhibition decreased AMCase secretion. Interestingly, AMCase secretion was not significantly altered by treatment with EGF but was significantly decreased when the upstream EGFR transactivator ADAM17 was inhibited. AMCase secretion was also decreased when the EGFR-downstream Ras was blocked. Transfected and recombinant AMCase induced epithelial cell production of CCL2, CCL17, and CXCL8. These studies demonstrate that lung epithelial cells secrete AMCase via an EGFR-dependent pathway that is activated by ADAM17 and mediates its effects via Ras. They also demonstrate that the AMCase that is secreted feeds back in an autocrine and/or paracrine fashion to stimulate pulmonary epithelial cell chemokine production.
Hartl
Dominik
D
Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8057, USA.
He
Chuan Hua
CH
Koller
Barbara
B
Da Silva
Carla A
CA
Homer
Robert
R
Lee
Chun G
CG
Elias
Jack A
JA
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D002688:Chitinases / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000378:metabolism; D014162:Transfection / Q000379:methods; D018631:ras Proteins / Q000378:metabolism
D018925:Chemokines; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; C499255:AMCase, mouse; C499254:CHIA protein, human; D002688:Chitinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; D018631:ras Proteins