The p38-MK2/3 Module Is Critical for IL-33–Induced Signaling and Cytokine Production in Dendritic Cells

Abstract

IL-33 is an IL-1 cytokine superfamily member. Binding of IL-33 to the IL-33R induces activation of the canonical NF-κB signaling and activation of MAPKs. In bone marrow–derived dendritic cells, IL-33 induces the production of IL-6, IL-13, and TNF-α. However, the signaling pathways resulting in IL-33–induced effector functions of dendritic cells are unknown. In this article, we show that the IL-33–induced cytokine production is only partly dependent on p65. Thereby, p65 mediates the production of IL-6, but not of IL-13, whereas the p38–Mapk-activated protein kinases 2/3 (MK2/3) signaling module mediates the IL-13, but not the IL-6, production. In addition, GM-CSF, which is critical for the differentiation and proliferation of bone marrow–derived dendritic cells, potentiates the p65-dependent IL-6 and the p38-MK2/3–dependent IL-13 production. Furthermore, we found that effective TNF-α production is only induced in the presence of GM-CSF and IL-33 via the p38-MK2/3 signaling module. Taken together, we found that the p38-MK2/3 signaling module is essential to mediate IL-33–induced cytokine production in dendritic cells.