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CCR7-Dependent Stimulation of Survival in Dendritic Cells Involves Inhibition of GSK3β¹

Department of Immunology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain

Chemokine receptor CCR7 regulates chemotaxis and survival in mature dendritic cells (DCs). We studied the role of glycogen synthase kinase-3β (GSK3β) in the regulation of CCR7-dependent survival. We show that GSK3β 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 GSK3β, 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-B and proapoptotic FOXO1, to the nucleus and cytosol, respectively, resulting in DCs with a phenotype more resistant to apoptotic stimuli. We analyzed if GSK3β was able to modulate the mobilizations of these transcription factors. Using pharmacological inhibitors, small interfering RNA, and a construct encoding constitutively active GSK3β, we show that active GSK3β fosters and hampers the translocations to the nucleus of FOXO and NF-B, respectively. Inhibition of GSK3β resulted in the degradation of the NF-B inhibitor IB, indicating a mechanism whereby GSK3 can control the translocation of NF-B to the nucleus. GSK3β and FOXO interacted in vivo, suggesting that this transcription factor could be a substrate of GSK3. The results provide a novel mechanism whereby active GSK3β contributes to regulate apoptosis in DCs. They also suggest that upon stimulation of CCR7, Akt-mediated phosphorylation/inhibition of GSK3β may be required to allow complete translocations of FOXO and NF-B that confer DCs an extended survival.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was partially supported by grants awarded to J.L.R.F. by Fundación Ramón Areces, Fundación Rodríguez Pascual, Ministerio de Educación y Ciencia (SAF2005-0081), RETICS Program/Instituto de Salud Carlos III (RIER) (RD08/0075), and Ministerio de Ciencia e Innovación (SAF2008-01468). C.E.D. and C.D.M. were recipients of I3P (Consejo Superior de Investigaciones Científicas-Fondo Social Europeo) and FPI Fellowships, respectively, conferred by the Ministerio de Educación y Ciencia (Spain).

² Address correspondence and reprint requests to Dr. José Luis Rodríguez-Fernández, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, C/Ramiro de Maeztu, 9, 28040 Madrid, Spain. E-mail address: rodrifer{at}cib.csic.es

³ Abbreviations used in this paper: DC, dendritic cell; _transd, -transducin; CMFDA, 5-chloromethylfluorescein diacetate; GSK3, glycogen synthase kinase-3; GSK3β-CA, constitutively active GSK3β; GS, glycogen synthase; LN, lymph node; PI, propidium iodide; PLL, poly-L-lysine; PTX, pertussis toxin; siRNA, small interfering RNA; SR, sulforhodamine B.