Chemokine receptor CCR7 induces intracellular signaling that inhibits apoptosis of mature dendritic cells.
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.
Sánchez-Sánchez
Noelia
N
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Riol-Blanco
Lorena
L
de la Rosa
Gonzalo
G
Puig-Kröger
Amaya
A
García-Bordas
Julio
J
Martín
Daniel
D
Longo
Natividad
N
Cuadrado
Antonio
A
Cabañas
Carlos
C
Corbí
Angel L
AL
Sánchez-Mateos
Paloma
P
Rodríguez-Fernández
José Luis
JL
D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D008855:Microscopy, Electron, Scanning; D016328:NF-kappa B / Q000502:physiology; D037342:Pertussis Toxin / Q000494:pharmacology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000502:physiology*; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
C515370:CCR7 protein, human; D016328:NF-kappa B; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D037342:Pertussis Toxin