Mst1-Deficiency Induces Hyperactivation of Monocyte-Derived Dendritic Cells via Akt1/c-myc Pathway

• Published in: Frontiers in immunology Vol. 10; p. 2142
• Main Authors: Cho, Kyung-Min, Kim, Myun Soo, Jung, Hak-Jun, Choi, Eui-Ju, Kim, Tae Sung
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 11.09.2019
• Subjects: Akt1; c-myc; dendritic cells; GM-CSF; hyperactivation; Immunology; Mst1; hyperactivation; Akt1; dendritic cells; c-myc; GM-CSF; Mst1
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2019.02142

Mst1 is a multifunctional serine/threonine kinase that is highly expressed in several immune organs. The role of Mst1 in the activation of dendritic cells (DCs), a key player of adaptive immunity, is poorly understood. In this study, we investigated the role of Mst1 in GM-CSF-induced bone marrow-derived DCs and the underlying mechanisms. DCs in response to GM-CSF expressed higher levels of activation/maturation-related cell surface molecules, such as B7 and MHC class II than DCs. Furthermore, the expression of proinflammatory cytokines, such as IL-23, TNF-α, and IL-12p40, was increased in DCs, indicating that Mst1-deficiency may induce the hyperactivation of DCs. Additionally, DCs exhibited a stronger capacity to activate allogeneic T cells than DCs. Silencing of Mst1 in DCs promoted their hyperactivation, similar to the phenotypes of DCs. DCs exhibited an increase in Akt1 phosphorylation and c-myc protein levels. In addition, treatment with an Akt1 inhibitor downregulated the protein level of c-myc increased in Mst1-deficient DCs, indicating that Akt1 acts as an upstream inducer of the synthesis of c-myc. Finally, Akt1 and c-myc inhibitors downregulated the increased expression of IL-23p19 observed in Mst1-knockdown DCs. Taken together, these data demonstrate that Mst1 negatively regulates the hyperactivation of DCs through downregulation of the Akt1/c-myc axis in response to GM-CSF, and suggest that Mst1 is one of the endogenous factors that determine the activation status of GM-CSF-stimulated inflammatory DCs.