|
pubmed:abstractText |
Chemokine receptor CCR7 regulates chemotaxis and survival in mature dendritic cells (DCs). We studied the role of glycogen synthase kinase-3beta (GSK3beta) in the regulation of CCR7-dependent survival. We show that GSK3beta 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 GSK3beta, 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-kappaB and proapoptotic FOXO1, to the nucleus and cytosol, respectively, resulting in DCs with a phenotype more resistant to apoptotic stimuli. We analyzed if GSK3beta was able to modulate the mobilizations of these transcription factors. Using pharmacological inhibitors, small interfering RNA, and a construct encoding constitutively active GSK3beta, we show that active GSK3beta fosters and hampers the translocations to the nucleus of FOXO and NF-kappaB, respectively. Inhibition of GSK3beta resulted in the degradation of the NF-kappaB inhibitor IkappaB, indicating a mechanism whereby GSK3 can control the translocation of NF-kappaB to the nucleus. GSK3beta and FOXO interacted in vivo, suggesting that this transcription factor could be a substrate of GSK3. The results provide a novel mechanism whereby active GSK3beta contributes to regulate apoptosis in DCs. They also suggest that upon stimulation of CCR7, Akt-mediated phosphorylation/inhibition of GSK3beta may be required to allow complete translocations of FOXO and NF-kappaB that confer DCs an extended survival.
|
