Loss of phosphoinositide 3-kinase gamma decreases migration and activation of phagocytes but not T cell activation in antigen-induced arthritis.
BACKGROUND
Phosphoinositide 3-kinase gamma (PI3Kgamma) has been depicted as a major regulator of inflammatory processes, including leukocyte activation and migration towards several chemokines. This study aims to explore the role of PI3Kgamma in the murine model of antigen-induced arthritis (AIA).


METHODS
Development of AIA was investigated in wildtype and PI3Kgamma-deficient mice as well as in mice treated with a specific inhibitor of PI3Kgamma (AS-605240) in comparison to untreated animals. Inflammatory reactions of leukocytes, including macrophage and T cell activation, and macrophage migration, were studied in vivo and in vitro.


RESULTS
Genetic deletion or pharmacological inhibition of PI3Kgamma induced a marked decrease of clinical symptoms in early AIA, together with a considerably diminished macrophage migration and activation (lower production of NO, IL-1beta, IL-6). Also, macrophage and neutrophil infiltration into the knee joint were impaired in vivo. However, T cell functions, measured by cytokine production (TNFalpha, IFNgamma, IL-2, IL-4, IL-5, IL-17) in vitro and DTH reaction in vivo were not altered, and accordingly, disease developed normally at later timepoints


CONCLUSIONS
PI3Kgamma specifically affects phagocyte function in the AIA model but has no impact on T cell activation.
Gruen
Michael
M
Institute of Pathology, University Hospital, Jena, Germany.
Rose
Christina
C
König
Christian
C
Gajda
Mieczyslaw
M
Wetzker
Reinhard
R
Bräuer
Rolf
R
D000818:Animals; D000941:Antigens / Q000494:pharmacology; D001168:Arthritis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D002465:Cell Movement / Q000235:genetics*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000235:genetics*; D058544:Class Ib Phosphatidylinositol 3-Kinase; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010586:Phagocytes / Q000201:enzymology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D013601:T-Lymphocytes / Q000201:enzymology / Q000378:metabolism
D000941:Antigens; D016207:Cytokines; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse