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PMID:15059845

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Citation

Sánchez-Sánchez, N, Riol-Blanco, L, de la Rosa, G, Puig-Kröger, A, García-Bordas, J, Martín, D, Longo, N, Cuadrado, A, Cabañas, C, Corbí, AL, Sánchez-Mateos, P and Rodríguez-Fernández, JL (2004) Chemokine receptor CCR7 induces intracellular signaling that inhibits apoptosis of mature dendritic cells. Blood 104:619-25

Abstract

Acquisition of CCR7 expression is an important phenotype change during dendritic cell (DC) maturation that endows these cells with the capability to migrate to lymph nodes. We have analyzed the possible role of CCR7 on the regulation of the survival of DCs. Stimulation with CCR7 ligands CCL19 and CCL21 inhibits apoptotic hallmarks of serum-deprived DCs, including membrane phosphatidylserine exposure, loss of mitochondria membrane potential, increased membrane blebs, and nuclear changes. Both chemokines induced a rapid activation of phosphatidylinositol 3'-kinase/Akt1 (PI3K/Akt1), with a prolonged and persistent activation of Akt1. Interference with PI3K, Gi, or G protein betagamma subunits abrogated the effects of the chemokines on Akt1 activation and on survival. In contrast, inhibition of extracellular signal-related kinase 1/2 (Erk1/2), p38, or c-Jun N-terminal kinase (JNK) was ineffective. Nuclear factor-kappaB (NFkappaB) was involved in the antiapoptotic effects of chemokines because inhibition of NFkappaB blunted the effects of CCL19 and CCL21 on survival. Furthermore, chemokines induced down-regulation of the NFkappaB inhibitor IkappaB, an increase of NFkappaB DNA-binding capability, and translocation of the NFkappaB subunit p65 to the nucleus. In summary, in addition to its well-established role in chemotaxis, we show that CCR7 also induces antiapoptotic signaling in mature DCs.

Links

PubMed Online version:10.1182/blood-2003-11-3943

Keywords

Apoptosis/physiology; Cell Differentiation/drug effects; Cell Survival; Dendritic Cells/cytology; Dendritic Cells/drug effects; Dendritic Cells/physiology; Dendritic Cells/ultrastructure; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology; Humans; Microscopy, Electron, Scanning; NF-kappa B/physiology; Pertussis Toxin/pharmacology; Receptors, CCR7; Receptors, Chemokine/physiology; Recombinant Proteins; Signal Transduction/physiology; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CCL21

involved_in

GO:2000669: negative regulation of dendritic cell apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCL21

involved_in

GO:0051897: positive regulation of protein kinase B signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCL21

involved_in

GO:0045860: positive regulation of protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCL21

involved_in

GO:0043552: positive regulation of phosphatidylinositol 3-kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCL21

involved_in

GO:0043123: positive regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCR7

involved_in

GO:2000669: negative regulation of dendritic cell apoptotic process

ECO:0000305: curator inference used in manual assertion

GO:0016493

P

Seeded From UniProt

complete

HUMAN:CCR7

involved_in

GO:0051897: positive regulation of protein kinase B signaling

ECO:0000305: curator inference used in manual assertion

GO:0016493

P

Seeded From UniProt

complete

HUMAN:CCR7

involved_in

GO:0045860: positive regulation of protein kinase activity

ECO:0000305: curator inference used in manual assertion

GO:0016493

P

Seeded From UniProt

complete

HUMAN:CCR7

involved_in

GO:0043552: positive regulation of phosphatidylinositol 3-kinase activity

ECO:0000305: curator inference used in manual assertion

GO:0016493

P

Seeded From UniProt

complete

HUMAN:CCR7

involved_in

GO:0043123: positive regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000305: curator inference used in manual assertion

GO:0016493

P

Seeded From UniProt

complete

HUMAN:CCL19

involved_in

GO:2000669: negative regulation of dendritic cell apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCL19

involved_in

GO:0051897: positive regulation of protein kinase B signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCL19

involved_in

GO:0045860: positive regulation of protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCL19

involved_in

GO:0043552: positive regulation of phosphatidylinositol 3-kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCL19

involved_in

GO:0043123: positive regulation of I-kappaB kinase/NF-kappaB signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CCL19

involved_in

GO:1901224: positive regulation of NIK/NF-kappaB signaling

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SDF1

involved_in

GO:2000669: negative regulation of dendritic cell apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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