Overexpression of CD39 in mouse airways promotes bacteria-induced inflammation.
In airways, the ecto-nucleoside triphosphate diphosphohydrolase CD39 plays a central role in the regulation of physiological mucosal nucleotide concentrations and likely contributes to the control of inflammation because accelerated ATP metabolism occurs in chronic inflammatory lung diseases. We sought to determine whether constant elevated CD39 activity in lung epithelia is sufficient to cause inflammation and whether this affects the response to acute LPS or Pseudomonas aeruginosa exposure. We generated transgenic mice overexpressing human CD39 under the control of the airway-specific Clara cell 10-kDa protein gene promoter. Transgenic mice did not develop any spontaneous lung inflammation. However, intratracheal instillation of LPS resulted in accelerated recruitment of neutrophils to the airways of transgenic mice. Macrophage clearance was delayed, and the amounts of CD8(+) T and B cells were augmented. Increased levels of keratinocyte chemoattractant, IL-6, and RANTES were produced in transgenic lungs. Similarly, higher numbers of neutrophils and macrophages were found in the lungs of transgenic mice infected with P. aeruginosa, which correlated with improved bacteria clearance. The transgenic phenotype was partially and differentially restored by coinstillation of P2X(1) or P2X(7) receptor antagonists or of caffeine with LPS. Thus, a chronic increase of epithelial CD39 expression and activity promotes airway inflammation in response to bacterial challenge by enhancing P1 and P2 receptor activation.
Interdisciplinary Cluster of Applied Genoproteomics-Inflammation, Infection, Immunity, Unit of Human Genetics, Laboratory of Thrombosis and Haemostasis, University of Liège, Liège 4000, Belgium.
Emilie
E
Théâtre
Kim
K
Frederix
William
W
Guilmain
Céline
C
Delierneux
Christelle
C
Lecut
Lucien
L
Bettendorff
Vincent
V
Bours
Cécile
C
Oury
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology*; D001081:Apyrase / Q000096:biosynthesis / Q000276:immunology*; D001424:Bacterial Infections / Q000276:immunology; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D011014:Pneumonia / Q000276:immunology* / Q000382:microbiology; D060888:Real-Time Polymerase Chain Reaction; D020545:Respiratory Mucosa / Q000276:immunology* / Q000382:microbiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015703:Antigens, CD; D001081:Apyrase; C067869:CD39 antigen