Bcl-2-mediated regulation of CD69-induced apoptosis of human eosinophils: identification and characterization of a novel receptor-induced mechanism and relationship to CD95-transduced signalling.
Elimination of the eosinophils from the airways by selective induction of apoptosis represents a therapeutic approach for asthma. Here we report on a possible target molecule, the surface receptor CD69. To simulate an asthmatic response, segmental allergen challenge in mild asthmatics was performed. Eosinophil numbers increased in bronchoalveolar lavage (BAL) at 18 h. In contrast to blood cells, BAL eosinophils expressed the activation marker CD69. Purified blood eosinophils stimulated with granulocyte/macrophage colony-stimulating factor (GM-CSF) or interferon-gamma (IFN-gamma) expressed CD69 and showed prolonged viability. Only IFN-gamma enhanced constitutive CD95 expression. Coincubation with anti-CD69 or anti-CD95 monoclonal antibody (MoAb) induced apoptosis, as revealed by propidium iodide incorporation, membrane blebbing and nuclear fragmentation. Additionally, both anti-CD69 and anti-CD95 MoAb reduced cytokine-enhanced Bcl-2 expression. In conclusion, CD69 transduces a Bcl-2-dependent death signal when ligated by a specific antibody. As, in contrast to the ubiquitous death-inducer CD95, the function of CD69 appears to be restricted to activated eosinophils, it represents an ideal target for therapeutic intervention in asthma.
Foerster
M
M
Pneumology, Medical Clinic IV, Friedrich-Schiller University, Jena, Germany. martin.foerster@med.uni-jena.de
Haefner
D
D
Kroegel
C
C
D000328:Adult; D000485:Allergens; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D001249:Asthma / Q000503:physiopathology; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid; D016084:Bronchoconstriction / Q000187:drug effects; D001999:Bronchoscopy; D002478:Cells, Cultured; D015195:Drug Design; D004804:Eosinophils / Q000166:cytology* / Q000187:drug effects; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D037181:Lectins, C-Type; D008297:Male; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D011940:Receptor Aggregation / Q000187:drug effects; D015398:Signal Transduction / Q000502:physiology*; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000099192:CD69 Antigens
D000485:Allergens; D018927:Anti-Asthmatic Agents; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D037181:Lectins, C-Type; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D019014:fas Receptor; D000099192:CD69 Antigens