Lung CD11c+ cells from mice deficient in Epstein-Barr virus-induced gene 3 (EBI-3) prevent airway hyper-responsiveness in experimental asthma.
Epstein-Barr virus-induced gene (EBI)-3 codes for a soluble type 1 cytokine receptor homologous to the p40 subunit of IL-12 that is expressed by antigen-presenting cells following activation. Here, we analyzed the functional role of EBI-3 in a murine model of asthma associated with airway hyper-responsiveness (AHR) in ovalbumin-sensitized mice. Upon allergen challenge, EBI-3-/- mice showed less severe AHR, decreased numbers and degranulation of eosinophils and a significantly reduced number of VCAM-1+ cells in the lungs as compared to wild-type littermates. We thus analyzed lung CD11c+ cells before and after allergen challenge in these mice and found that before allergen challenge, lung CD11c+ cells isolated from EBI-3-/- mice express markers of a more plasmacytoid phenotype without releasing IFN-alpha as compared to those from wild-type littermates. Moreover, allergen challenge induced the development of myeloid CD11c+ cells in the lungs of EBI-3-/- mice, which released increased amounts of IL-10 and IL-12 while not expressing IFN-alpha. Finally, inhibition of EBI-3 expression in lung DC could prevent AHR in adoptive transfer studies by suppressing mediator release of effector cells into the airways. These results indicate a novel role for EBI-3 in controlling local immune responses in the lungs in experimental asthma.
Hausding
Michael
M
Laboratory of Cellular and Molecular Lung Immunology, I Medical Clinic, University of Mainz, Mainz, Germany, and Institut Universitaire de Pathologie Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Karwot
Roman
R
Scholtes
Petra
P
Lehr
Hans A
HA
Wegmann
Michael
M
Renz
Harald
H
Galle
Peter R
PR
Birkenbach
Mark
M
Neurath
Markus F
MF
Blumberg
Richard S
RS
Finotto
Susetta
S
D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D039521:CD11c Antigen / Q000032:analysis*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D017690:Cell Transplantation / Q000379:methods; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D004804:Eosinophils / Q000378:metabolism / Q000473:pathology; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine / Q000235:genetics*; D050797:STAT4 Transcription Factor / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000098815:T-bet Transcription Factor
D039521:CD11c Antigen; C499601:Ebi3 protein, mouse; D016898:Interferon-alpha; D015848:Interleukin-5; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma