CCR7-Dependent Stimulation of Survival in Dendritic Cells Involves Inhibition of GSK3β

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.