Role of the Immune Cell Cytoskeleton in Breast Cancer Immunity: Particular Relationship Between Actin and p38 MAP Kinase

摘要

Deformation of the cytoskeleton activates intracellular signaling pathways, including those governing differentiation. Based on the observation that monocytes reverse transmigrating through endothelial cells spontaneously undergo differentiation into dendritic cells (DCs), we hypothesized that the cytoskeleton modulation could affect DC differentiation. Monocytes were cultured with granulocyte M-CSF (GM-CSF) plus IL-4 to induce differentiation into immature DCs. The microtubule stabilizer paclitaxel significantly reduced DC cd1a and CD40 without affecting CD54, CD80 and MHC class I expression. DCs differentiating in the presence of paclitaxel secreted significantly (>55%) less IL-12 and significantly (4-fold) more IL-10 compared to control DCs following LPS-induced maturation. As a result, DCs differentiating in the presence of paclitaxel induced 9-fold less T cell interferon-gamma compared to control DCs, and were inefficient at activating T cells. The microtubule destabilizer nocodazole reversed paclitaxel effects on DCs in a dose-dependent fashion, suggesting that derangements of microtubule movement and architecture were responsible for paclitaxel effects. Whereas LPS effects on differentiation are relatively irreversible, paclitaxel effects were reversible within 48 hours of paclitaxel withdrawal. Microtubules play an essential role in DC phagocytosis and migration. These data suggest that microtubules also mediate non-phagocytic DC functions including differentiation and T cell activation.