期刊
JOURNAL OF IMMUNOLOGY
卷 183, 期 10, 页码 6282-6295出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0804093
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资金
- Fundacion Ramon Areces, Fundacion Rodriguez Pascual, Ministerio de Educacion y Ciencia [SAF2005-0081]
- RETICS Program/Instituto de Salud Carlos III (RIER) [RD08/0075]
- Ministerio de Ciencia e Innovacion [SAF2008-01468]
- I3P (Consejo Superior de Investigaciones Cientificas-Fondo Social Europeo)
Chemokine receptor CCR7 regulates chemotaxis and survival in mature dendritic cells (DCs). We studied the role of glycogen synthase kinase-3 beta (GSK3 beta) in the regulation of CCR7-dependent survival. We show that GSK3 beta behaves as a proapoptotic regulator in cultured monocyte-derived human DCs and murine splenic DCs in vitro, and in lymph node DCs in vivo. In keeping with its prosurvival role, stimulation of CCR7 induced phosphorylation/inhibition of GSK3 beta, which was mediated by the prosurvival regulator Akt1, but it was independent of ERK1/2, a key regulator of chemotaxis. Stimulation of CCR7 also induced translocation of two transcription-factor targets of Akt, prosurvival NF-kappa B and proapoptotic FOXO1, to the nucleus and cytosol, respectively, resulting in DCs with a phenotype more resistant to apoptotic stimuli. We analyzed if GSK3 beta was able to modulate the mobilizations of these transcription factors. Using pharmacological inhibitors, small interfering RNA, and a construct encoding constitutively active GSK3 beta, we show that active GSK3 beta fosters and hampers the translocations to the nucleus of FOXO and NF-kappa B, respectively. Inhibition of GSK3 beta resulted in the degradation of the NF-kappa B inhibitor I kappa B, indicating a mechanism whereby GSK3 can control the translocation of NF-kappa B to the nucleus. GSK3 beta and FOXO interacted in vivo, suggesting that this transcription factor could be a substrate of GSK3. The results provide a novel mechanism whereby active GSK3 beta contributes to regulate apoptosis in DO. They also suggest that upon stimulation of CCR7, Akt-mediated phosphorylation/inhibition of GSK3 beta may be required to allow complete translocations of FOXO and NF-kappa B that confer DCs an extended survival. The Journal of Immunology, 2009, 183: 6282-6295.
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