title: p110γ/δ Double-Deficiency Induces Eosinophilia and IgE Production but Protects from OVA-Induced Airway Inflammation.
abstract: The catalytical isoforms p110γ and p110δ of phosphatidylinositide 3-kinase γ (PI3Kγ) and PI3Kδ play an important role in the pathogenesis of asthma. Two key elements in allergic asthma are increased levels of eosinophils and IgE. Dual pharmacological inhibition of p110γ and p110δ reduces asthma-associated eosinophilic lung infiltration and ameliorates disease symptoms, whereas the absence of enzymatic activity in p110γKOδD910A mice increases IgE and basal eosinophil counts. This suggests that long-term inhibition of p110γ and p110δ might exacerbate asthma. Here, we analysed mice genetically deficient for both catalytical subunits (p110γ/δ-/-) and determined basal IgE and eosinophil levels and the immune response to ovalbumin-induced asthma. Serum concentrations of IgE, IL-5 and eosinophil numbers were significantly increased in p110γ/δ-/- mice compared to single knock-out and wildtype mice. However, p110γ/δ-/- mice were protected against OVA-induced infiltration of eosinophils, neutrophils, T and B cells into lung tissue and bronchoalveolar space. Moreover, p110γ/δ-/- mice, but not single knock-out mice, showed a reduced bronchial hyperresponsiveness. We conclude that increased levels of eosinophils and IgE in p110γ/δ-/- mice do not abolish the protective effect of p110γ/δ-deficiency against OVA-induced allergic airway inflammation.
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology and ICePhA, University of Tuebingen, 72074 Tuebingen, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Mothes
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology and ICePhA, University of Tuebingen, 72074 Tuebingen, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Bucher
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute for Pharmacy, University of Tuebingen, 72076 Tuebingen, Germany.|Department of Clinical Pharmacology and ICePhA, University of Tuebingen, and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Ammon-Treiber
authors.affiliation: Department of Clinical Pharmacology and ICePhA, University of Tuebingen, and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.affiliation: Institutes for Biochemistry and Molekular Biology II, University of Duesseldorf, 40225 Duesseldorf, Germany.
authors.forename: Roland P
authors.initials: RP
authors.lastname: Piekorz
authors.affiliation: Department of Genetics, Biology and Biochemistry, University of Torino, 10126 Torino, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology and ICePhA, University of Tuebingen, 72074 Tuebingen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Nürnberg
authors.affiliation: Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and Toxicology and ICePhA, University of Tuebingen, 72074 Tuebingen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Beer-Hammer
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000097:blood / Q000150:complications / Q000201:enzymology / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002452:Cell Count; D058534:Class I Phosphatidylinositol 3-Kinases / Q000172:deficiency* / Q000378:metabolism; D004802:Eosinophilia / Q000097:blood / Q000150:complications / Q000201:enzymology* / Q000276:immunology*; D004804:Eosinophils / Q000276:immunology; D020397:Goblet Cells / Q000473:pathology; D006967:Hypersensitivity / Q000097:blood / Q000150:complications / Q000201:enzymology / Q000276:immunology; D007073:Immunoglobulin E / Q000096:biosynthesis*; D015848:Interleukin-5 / Q000097:blood; D008168:Lung / Q000276:immunology / Q000473:pathology; D008679:Metaplasia; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology*; D011014:Pneumonia / Q000097:blood / Q000150:complications / Q000201:enzymology* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D015848:Interleukin-5; D007073:Immunoglobulin E; D010047:Ovalbumin; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases