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PMID:18824549

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Citation

Hartl, D, He, CH, Koller, B, Da Silva, CA, Homer, R, Lee, CG and Elias, JA (2008) Acidic mammalian chitinase is secreted via an ADAM17/epidermal growth factor receptor-dependent pathway and stimulates chemokine production by pulmonary epithelial cells. J. Biol. Chem. 283:33472-82

Abstract

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.

Links

PubMed PMC2586247 Online version:10.1074/jbc.M805574200

Keywords

ADAM Proteins/genetics; ADAM Proteins/metabolism; Animals; Cell Line; Chemokines/genetics; Chemokines/secretion; Chitinase/genetics; Chitinase/secretion; Epidermal Growth Factor/metabolism; Epithelial Cells/cytology; Epithelial Cells/secretion; Humans; Inflammation/genetics; Inflammation/metabolism; Lung/cytology; Lung/secretion; Mice; Mice, Transgenic; Receptor, Epidermal Growth Factor/genetics; Receptor, Epidermal Growth Factor/metabolism; Respiratory Mucosa/cytology; Respiratory Mucosa/secretion; Th2 Cells/cytology; Th2 Cells/secretion; Transfection/methods; ras Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:EGFR

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9BZP6

F

Seeded From UniProt

complete

MOUSE:CHIA

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CHIA

enables

GO:0004568: chitinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:CHIA

enables

GO:0019900: kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P00533

F

Seeded From UniProt

complete

HUMAN:CHIA

involved_in

GO:0002532: production of molecular mediator involved in inflammatory response

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CHIA

located_in

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CHIA

involved_in

GO:0032722: positive regulation of chemokine production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CHIA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P00533

F

Seeded From UniProt

complete

HUMAN:EGFR_original

GO:0005515: protein binding

IPI: Inferred from Physical Interaction: UniProtKB:Q9BZP6

F



See also

References

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