PI3K-Akting in crosstalk between Notch1-Jagged2 and CD28-B7 pathways in dendritic cells (165.21)

Abstract

Abstract Survival of myeloma cells is characterized by their critical interaction with bone marrow stromal cells, which produce IL-6. At the cellular level, dendritic cells (DC) in the bone marrow microenvironment and at the molecular level the CD28-B7 and Notch1-Jagged2 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 B7, a ligand with a short cytoplasmic tail, is largely uncharacterized. Inhibiting Notch signaling using pharmacological inhibitors and blocking antibodies leads to a significant decrease in CD28 mediated IL-6 production by DC suggesting crosstalk between the Notch1-Jagged2 and CD28-B7 pathways. To underline the molecular mechanism of crosstalk, we blocked PI3K and PKC activity using Ly294002 and Bis respectively and observed a significant decrease in IL-6 production upon B7 crosslinking. Additionally, CD28 mediated crosslinking of B7 in DC leads to activation of P-Akt(Thr 308) thus implicating the PI3K-Akt pathway downstream of B7 which is a novel finding. We are examining the potential role of PTEN downstream of Notch signaling in crosstalk in both human and murine DC by testing its effect on P-Akt expression. Targeting IL-6 induced by crosstalk between these two pathways prompts not only clinical evaluation to improve MM patient outcome but also extends to advancing knowledge in T-cell biology and normal plasma cell biology.