The PtdIns 3-Kinase/Akt Pathway Regulates Macrophage-Mediated ADCC against B Cell Lymphoma
Autor: | Natarajan Muthusamy, Michael C. Ostrowski, Susheela Tridandapani, Trupti Joshi, Carolyn Cheney, Latha P. Ganesan, John C. Byrd |
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Rok vydání: | 2009 |
Předmět: |
Cytotoxicity
Immunologic Lymphoma B-Cell Immunology/Innate Immunity Immunology/Immunomodulation lcsh:Medicine Biology Nitric Oxide Cell Biology/Cell Signaling Antibodies Monoclonal Murine-Derived Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Cell Adhesion Tumor Cells Cultured Animals Humans Macrophage lcsh:Science Cell adhesion Protein kinase B PI3K/AKT/mTOR pathway 030304 developmental biology Antibody-dependent cell-mediated cytotoxicity 0303 health sciences Multidisciplinary Kinase Macrophages lcsh:R Antibody-Dependent Cell Cytotoxicity Antibodies Monoclonal 3. Good health Raji cell Cell biology lcsh:Q Signal transduction Rituximab Proto-Oncogene Proteins c-akt Research Article 030215 immunology |
Zdroj: | PLoS ONE PLoS ONE, Vol 4, Iss 1, p e4208 (2009) |
ISSN: | 1932-6203 |
Popis: | 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. |
Databáze: | OpenAIRE |
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