The PtdIns 3-kinase/Akt pathway regulates macrophage-mediated ADCC against B cell lymphoma.
Macrophages are important effectors in the clearance of antibody-coated tumor cells. However, the signaling pathways that regulate macrophage-induced ADCC are poorly defined. To understand the regulation of macrophage-mediated ADCC, we used human B cell lymphoma coated with Rituximab as the tumor target and murine macrophages primed with IFNgamma as the effectors. Our data demonstrate that the PtdIns 3-kinase/Akt pathway is activated during macrophage-induced ADCC and that the inhibition of PtdIns 3-kinase results in the inhibition of macrophage-mediated cytotoxicity. Interestingly, downstream of PtdIns 3-kinase, expression of constitutively active Akt (Myr-Akt) in macrophages significantly enhanced their ability to mediate ADCC. Further analysis revealed that in this model, macrophage-mediated ADCC is dependent upon the release of nitric oxide (NO). However, the PtdIns 3-kinase/Akt pathway does not appear to regulate NO production. An examination of the role of the PtdIns 3-kinase/Akt pathway in regulating conjugate formation indicated that macrophages treated with an inhibitor of PtdIns 3-kinase fail to polarize the cytoskeleton at the synapse and show a significant reduction in the number of conjugates formed with tumor targets. Further, inhibition of PtdIns 3-kinase also reduced macrophage spreading on Rituximab-coated surfaces. On the other hand, Myr-Akt expressing macrophages displayed a significantly greater ability to form conjugates with tumor cells. Taken together, these findings illustrate that the PtdIns 3-kinase/Akt pathway plays a critical role in macrophage ADCC through its influence on conjugate formation between macrophages and antibody-coated tumor cells.
Joshi
Trupti
T
The Ohio State University Biochemistry Program, The Ohio State University, Columbus, Ohio, USA.
Ganesan
Latha P
LP
Cheney
Carolyn
C
Ostrowski
Michael C
MC
Muthusamy
Natarajan
N
Byrd
John C
JC
Tridandapani
Susheela
S
D000818:Animals; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D002448:Cell Adhesion; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000069283:Rituximab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D009569:Nitric Oxide; D000069283:Rituximab; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt