Role of PI3K-Akt in crosstalk between Notch and CD28-CD80/86 pathways in dendritic cell “backsignaling” (162.2)

Abstract

Abstract Survival of myeloma cells is characterized by their interaction with bone marrow stromal cells, which produce critical soluble factors including IL-6 and IDO. Targeting pathways involved in production of factors which are important in myeloma cell biology, provides novel therapeutic targets for a disease which otherwise remains incurable. At the cellular level, dendritic cells (DC) in the bone marrow microenvironment and at the molecular level the CD28-CD80/86 and Notch-Jagged pathways were separately implicated by us in myeloma induced IL-6 production. While Notch signaling leading to IL-6 production in DC is well understood, the mechanism of “backsignaling” via CD80/86- ligands with short cytoplasmic tails, remains largely uncharacterized. We demonstrate that inhibiting Notch signaling leads to a significant decrease in CD28 mediated IL-6 and IDO production by DC, suggesting crosstalk between Notch and CD28-CD80/86 pathways. IL-6 production by dendritic cells, upon ligation of CD80/86 by CD28-Ig, involves the PI3K-Akt-FoxO3a axis, which has not been previously established. Furthermore, we demonstrate a novel crosstalk between Notch and CD80/86 signaling involving regulation of the PI3K-Akt pathway by casein kinase and PTEN, which in turn are regulated by Notch signaling. Targeting pathways involved in IL-6 and IDO prompts not only clinical evaluation to improve MM patient outcome but also extends to advancing knowledge in T-cells and normal plasma cell biology.