Chemokine receptor CCR7 induces intracellular signaling that inhibits apoptosis of mature dendritic cells

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 ␤␥ 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-B (NFB) was involved in the antiapoptotic effects of chemokines because inhibition of NFB blunted the effects of CCL19 and CCL21 on survival. Furthermore, chemokines induced down-regulation of the NFB inhibitor IB, an increase of NFB DNA-binding capability, and translocation of the NFB 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. IntroductionApoptosis, or programmed cell death, is a physiologic process involved in the normal development and maintenance of tissue homeostasis. 1 The final stage of this process that leads to the demise of the cell is executed by proteases that degrade vital molecular components of the cell. 1 Hallmarks of cells undergoing apoptosis include disruption of mitochondria transmembrane potential, apparition of numerous blebs on the membrane, increased nuclear condensation, and increased appearance of phosphatidylserine (PS) in the outer leaflet of the cell membrane.Apoptosis is a programmed process that is regulated through a complex mechanism that involves multiple molecular intermediates. Surface receptors may inhibit apoptosis by relaying intracellular signals that either repress proapoptotic molecules and/or stimulate antiapoptotic ones. 1 Multiple pathways that inhibit apoptosis use as a common signaling intermediate phosphatidylinositol 3Ј-kinase (PI3K) and its downstream effector Akt1. 1-3 Akt1 phosphorylates and inhibits a variety of proapoptotic regulators and also regulates proteins that promote cell survival. [1][2][3] In this regard, it has been shown that Akt1 may activate IB kinase, which induces phosphorylation and subsequent degradation of IB, a molecule that binds and retains transcription factor nuclear factor-B (NFB) in the cytoplasm. 1-3 Upon IB degradation, NFB translocates to the nucleus and stimulates transcription from a variety of antiapoptotic genes. 2,4 Apart from PI3K/Akt1, in some cell settings, mitogen-activated protein kinase (MAPK) family members have also been shown to play an important role as regulators of apoptosis. [5][6][7] Dendritic ...

Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

“…In addition, it was shown that elevations of intracellular calcium are not necessary for directional migration of mouse neutrophils [36]. However, a recent publication, dealing with the dissection of chemokine receptor transduced signaling pathways, showed clearly that, in human monocyte-derived DC, chemokineinduced migration through CCR7 depended on the MAPK pathways, especially on ERK1/2 activity, whereas signaling through the PI3Kc/PKB pathway was responsible for mediating anti-apoptotic effects but not chemotaxis [34,51,52]. Apart from that, by comparing the impact between CCR7 and CXCR4 engagement on mature DC, we found a close association between ERK activity, especially ERK-1 activity, and the outcome of a chemotactic response in human monocyte-derived DC [33].…”

Chemokine receptor 7 activates phosphoinositide-3 kinase-mediated invasive and prosurvival pathways in head and neck cancer cells independent of EGFR

“…Recently, metastatic SCCHN cells have been shown to express chemokine receptor 7 (CCR7), which may enable their access to the lymphatic system and facilitate spread to regional lymph nodes (Wang et al, 2004). Immune cells utilize CCR7 to transmit a prosurvival signal, mediated by the phosphoinositide-3 kinase (PI3K)/protein kinase B (PKB/Akt) cascade (Pilkington et al, 2004;Sa´nchez-Sa´nchez et al, 2004), which may be analogous in epithelial cancer cells. In order to determine the mechanism(s) by which chemokines promote tumor growth and spread, we have studied the downstream events mediating CCR7-induced migration, invasion, and survival in metastatic SCCHN cells.…”

Expression of CC chemokine receptor 7 in tonsillar cancer predicts cervical nodal metastasis, systemic relapse and survival

“…This observation may have been due, at least in part, to the effects of CCR7 on resistance to adjuvant radiation therapy. Since CCR7 signalling in normal immune cells mediates a pro-survival signal through the PKB/AKT cascade (Pilkington et al, 2004;Sanchez-Sanchez et al, 2004), it is also possible that this pathway may influence outcome in response to treatment in head and neck cancers. Therefore, patients with primary tumours that express high levels of CCR7 may be good candidates for enrolment in studies of new agents that target the CCR7-PI-3K-PKB/AKT axis.…”