Serum- and Glucocorticoid-Inducible Kinase 1 Sensitive NF-κB Signaling in Dendritic Cells

Cellular Physiology and Biochemistry

关键词: NF-κB;    IKKα/β;    PI3 kinase;    NDRG1;    Phagocytosis;   

DOI  :  10.1159/000366311

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background/Aims Dendritic cells (DCs), antigen-presenting cells linking innate and adaptive immunity, are required for initiation of specific T cell-driven immune responses. Phosphoinositide-3-kinase (PI3K) suppresses proinflammatory cytokine production in DCs, which limits T helper (Th1) polarization. PI3K is in part effective by downregulation of transcription factor NF-κB. Downstream signaling elements of PI3K include serum- and glucocorticoid-inducible kinase 1 (SGK1) and its phosphorylation target N-myc downstream regulated gene 1 (NDRG1). The present study explored whether SGK1 and NDRG1 play a role in the regulation of NF-κB and DC-maturation. Methods DCs were isolated from bone marrow (BMDCs) or spleen of mice lacking functional SGK1 (sgk1^-/-) and corresponding wild type mice (sgk1^+/+). Protein abundance was determined by Western blotting. Transcription was inhibited by siRNA. Abundance of maturation markers was quantified by flow cytometry. FITC-dextran uptake was determined to quantify phagocytosis. Results NDRG1 was similarly expressed in sgk1^+/+ and sgk1^-/-BMDCs, but SGK1-dependent phosphorylation of NDRG-1 was decreased in sgk1^-/-BMDCs. Silencing of NDRG1 in sgk1^+/+BMDCs as compared to control empty vector-treated BMDCs enhanced nuclear abundance of NF-κB subunit p65. Moreover, the abundance of phosphorylated NF-κB inhibitor IκBa, of phosphorylated IκB kinase (IKKa/ß) and of nuclear p65 were significantly higher in sgk1^-/-BMDCs than in sgk1^+/+BMDCs. Expression of maturation markers, MHC II, and CD86, was significantly larger and phagocytic capacity was significantly lower in sgk1^-/- than in sgk1^+/+BMDCs. Expression of CD86 and MHCII was also significantly higher in DCs isolated from the spleen of sgk1^-/- mice than those from sgk1^+/+mice. Conclusion SGK1 and NDRG1 participate in the regulation of NF-κB signaling in and maturation of DCs.

【 授权许可】

CC BY-NC-ND