Combining with a C-C chemokine and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity. C-C chemokines do not have an amino acid between the first two cysteines of the characteristic four-cysteine motif.
Combining with the C-C motif chemokine 19 (CCL19) and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity.
J. Biol. Chem. 273, 7118-7122 (1998)[PubMed:9507024]
Secondary Lymphoid-tissue Chemokine (SLC) is a recently identified CC chemokine that is constitutively expressed in various lymphoid tissues and is a potent and specific chemoattractant for lymphocytes. The SLC gene and the gene encoding another lymphocyte-specific CC chemokine, EBI1-ligand chemokine (ELC), form a mini-cluster at human chromosome 9p13. Here, we show that SLC is a high affinity functional ligand for chemokine receptor 7 (CCR7) that is expressed on T and B lymphocytes and a known receptor for ELC. SLC induced a vigorous calcium mobilization in murine L1.2 cells stably expressing human CCR7. SLC tagged with the secreted form of alkaline phosphatase (SLC-SEAP) showed specific binding to CCR7 that was fully competed by SLC with an IC50 of 0.5 nM. SLC also induced a vigorous chemotactic response in CCR7-expressing L1.2 cells with a typical bell-shaped dose-response curve and a maximal migration at 10 nM. When assessed using CCR7-transfected L1.2 cells, SLC and ELC were essentially equivalent in terms of cross desensitization in calcium mobilization via CCR7, cross-competition in binding to CCR7, and induction of chemotaxis via CCR7. SLC and ELC were also shown to fully share receptors expressed on cultured normal T cells known to express CCR7. Notably, however, SLC was somehow less efficient in cross-desensitization against ELC in calcium mobilization and in cross-competition with ELC for binding when assessed using cultured normal T cells. Thus, SLC and ELC, even though sharing only 32% amino acid identity, constitute a genetically and functionally highly related subgroup of CC chemokines.
Combining with the C-C motif chemokine 21 (CCL21) and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity.
J. Biol. Chem. 273, 7118-7122 (1998)[PubMed:9507024]
Secondary Lymphoid-tissue Chemokine (SLC) is a recently identified CC chemokine that is constitutively expressed in various lymphoid tissues and is a potent and specific chemoattractant for lymphocytes. The SLC gene and the gene encoding another lymphocyte-specific CC chemokine, EBI1-ligand chemokine (ELC), form a mini-cluster at human chromosome 9p13. Here, we show that SLC is a high affinity functional ligand for chemokine receptor 7 (CCR7) that is expressed on T and B lymphocytes and a known receptor for ELC. SLC induced a vigorous calcium mobilization in murine L1.2 cells stably expressing human CCR7. SLC tagged with the secreted form of alkaline phosphatase (SLC-SEAP) showed specific binding to CCR7 that was fully competed by SLC with an IC50 of 0.5 nM. SLC also induced a vigorous chemotactic response in CCR7-expressing L1.2 cells with a typical bell-shaped dose-response curve and a maximal migration at 10 nM. When assessed using CCR7-transfected L1.2 cells, SLC and ELC were essentially equivalent in terms of cross desensitization in calcium mobilization via CCR7, cross-competition in binding to CCR7, and induction of chemotaxis via CCR7. SLC and ELC were also shown to fully share receptors expressed on cultured normal T cells known to express CCR7. Notably, however, SLC was somehow less efficient in cross-desensitization against ELC in calcium mobilization and in cross-competition with ELC for binding when assessed using cultured normal T cells. Thus, SLC and ELC, even though sharing only 32% amino acid identity, constitute a genetically and functionally highly related subgroup of CC chemokines.
J. Biol. Chem. 273, 7118-7122 (1998)[PubMed:9507024]
Secondary Lymphoid-tissue Chemokine (SLC) is a recently identified CC chemokine that is constitutively expressed in various lymphoid tissues and is a potent and specific chemoattractant for lymphocytes. The SLC gene and the gene encoding another lymphocyte-specific CC chemokine, EBI1-ligand chemokine (ELC), form a mini-cluster at human chromosome 9p13. Here, we show that SLC is a high affinity functional ligand for chemokine receptor 7 (CCR7) that is expressed on T and B lymphocytes and a known receptor for ELC. SLC induced a vigorous calcium mobilization in murine L1.2 cells stably expressing human CCR7. SLC tagged with the secreted form of alkaline phosphatase (SLC-SEAP) showed specific binding to CCR7 that was fully competed by SLC with an IC50 of 0.5 nM. SLC also induced a vigorous chemotactic response in CCR7-expressing L1.2 cells with a typical bell-shaped dose-response curve and a maximal migration at 10 nM. When assessed using CCR7-transfected L1.2 cells, SLC and ELC were essentially equivalent in terms of cross desensitization in calcium mobilization via CCR7, cross-competition in binding to CCR7, and induction of chemotaxis via CCR7. SLC and ELC were also shown to fully share receptors expressed on cultured normal T cells known to express CCR7. Notably, however, SLC was somehow less efficient in cross-desensitization against ELC in calcium mobilization and in cross-competition with ELC for binding when assessed using cultured normal T cells. Thus, SLC and ELC, even though sharing only 32% amino acid identity, constitute a genetically and functionally highly related subgroup of CC chemokines.
J. Biol. Chem. 273, 7118-7122 (1998)[PubMed:9507024]
Secondary Lymphoid-tissue Chemokine (SLC) is a recently identified CC chemokine that is constitutively expressed in various lymphoid tissues and is a potent and specific chemoattractant for lymphocytes. The SLC gene and the gene encoding another lymphocyte-specific CC chemokine, EBI1-ligand chemokine (ELC), form a mini-cluster at human chromosome 9p13. Here, we show that SLC is a high affinity functional ligand for chemokine receptor 7 (CCR7) that is expressed on T and B lymphocytes and a known receptor for ELC. SLC induced a vigorous calcium mobilization in murine L1.2 cells stably expressing human CCR7. SLC tagged with the secreted form of alkaline phosphatase (SLC-SEAP) showed specific binding to CCR7 that was fully competed by SLC with an IC50 of 0.5 nM. SLC also induced a vigorous chemotactic response in CCR7-expressing L1.2 cells with a typical bell-shaped dose-response curve and a maximal migration at 10 nM. When assessed using CCR7-transfected L1.2 cells, SLC and ELC were essentially equivalent in terms of cross desensitization in calcium mobilization via CCR7, cross-competition in binding to CCR7, and induction of chemotaxis via CCR7. SLC and ELC were also shown to fully share receptors expressed on cultured normal T cells known to express CCR7. Notably, however, SLC was somehow less efficient in cross-desensitization against ELC in calcium mobilization and in cross-competition with ELC for binding when assessed using cultured normal T cells. Thus, SLC and ELC, even though sharing only 32% amino acid identity, constitute a genetically and functionally highly related subgroup of CC chemokines.
Combining with an extracellular signal and transmitting the signal across the membrane by activating an associated G-protein; promotes the exchange of GDP for GTP on the alpha subunit of a heterotrimeric G-protein complex.
J. Immunol. 176, 5153-5159 (2006)[PubMed:16621978]
CCR7 was described initially as a potent leukocyte chemotactic receptor that was later shown to be responsible of directing the migration of dendritic cells (DCs) to the lymph nodes where these cells play an important role in the initiation of the immune response. Recently, a variety of reports have indicated that, apart from chemotaxis, CCR7 controls the cytoarchitecture, the rate of endocytosis, the survival, the migratory speed, and the maturation of the DCs. Some of these functions of CCR7 and additional ones also have been described in other cell types. Herein we discuss how this receptor may contribute to modulate the immune response by regulating different functions in DCs. Finally, we also suggest a possible mechanism whereby CCR7 may control its multiple tasks in these cells.
J. Immunol. 174, 4070-4080 (2005)[PubMed:15778365]
CCR7 is necessary to direct dendritic cells (DCs) to secondary lymphoid nodes and to elicit an adaptative immune response. Despite its importance, little is known about the molecular mechanisms used by CCR7 to direct DCs to lymph nodes. In addition to chemotaxis, CCR7 regulates the migratory speed of DCs. We investigated the intracellular pathways that regulate CCR7-dependent chemotaxis and migratory speed. We found that CCR7 induced a G(i)-dependent activation of MAPK members ERK1/2, JNK, and p38, with ERK1/2 and p38 controlling JNK. MAPK members regulated chemotaxis, but not the migratory speed, of DCs. CCR7 induced activation of PI3K/Akt; however, these enzymes did not regulate either chemotaxis or the speed of DCs. CCR7 also induced activation of the GTPase Rho, the tyrosine kinase Pyk2, and inactivation of cofilin. Pyk2 activation was independent of G(i) and Src and was dependent on Rho. Interference with Rho or Pyk2 inhibited cofilin inactivation and the migratory speed of DCs, but did not affect chemotaxis. Interference with Rho/Pyk2/cofilin inhibited DC migratory speed even in the absence of chemokines, suggesting that this module controls the speed of DCs and that CCR7, by activating its components, induces an increase in migratory speed. Therefore, CCR7 activates two independent signaling modules, one involving G(i) and a hierarchy of MAPK family members and another involving Rho/Pyk2/cofilin, which control, respectively, chemotaxis and the migratory speed of DCs. The use of independent signaling modules to control chemotaxis and speed can contribute to regulate the chemotactic effects of CCR7.
A series of molecular signals initiated by the binding of the C-C chemokine CCL19 to a receptor on the surface of a cell, and ending with regulation of a downstream cellular process, e.g. transcription.
J. Biol. Chem. 273, 7118-7122 (1998)[PubMed:9507024]
Secondary Lymphoid-tissue Chemokine (SLC) is a recently identified CC chemokine that is constitutively expressed in various lymphoid tissues and is a potent and specific chemoattractant for lymphocytes. The SLC gene and the gene encoding another lymphocyte-specific CC chemokine, EBI1-ligand chemokine (ELC), form a mini-cluster at human chromosome 9p13. Here, we show that SLC is a high affinity functional ligand for chemokine receptor 7 (CCR7) that is expressed on T and B lymphocytes and a known receptor for ELC. SLC induced a vigorous calcium mobilization in murine L1.2 cells stably expressing human CCR7. SLC tagged with the secreted form of alkaline phosphatase (SLC-SEAP) showed specific binding to CCR7 that was fully competed by SLC with an IC50 of 0.5 nM. SLC also induced a vigorous chemotactic response in CCR7-expressing L1.2 cells with a typical bell-shaped dose-response curve and a maximal migration at 10 nM. When assessed using CCR7-transfected L1.2 cells, SLC and ELC were essentially equivalent in terms of cross desensitization in calcium mobilization via CCR7, cross-competition in binding to CCR7, and induction of chemotaxis via CCR7. SLC and ELC were also shown to fully share receptors expressed on cultured normal T cells known to express CCR7. Notably, however, SLC was somehow less efficient in cross-desensitization against ELC in calcium mobilization and in cross-competition with ELC for binding when assessed using cultured normal T cells. Thus, SLC and ELC, even though sharing only 32% amino acid identity, constitute a genetically and functionally highly related subgroup of CC chemokines.
A series of molecular signals initiated by the binding of the C-C chemokine CCL21 to a receptor on the surface of a cell, and ending with regulation of a downstream cellular process, e.g. transcription.
J. Biol. Chem. 273, 7118-7122 (1998)[PubMed:9507024]
Secondary Lymphoid-tissue Chemokine (SLC) is a recently identified CC chemokine that is constitutively expressed in various lymphoid tissues and is a potent and specific chemoattractant for lymphocytes. The SLC gene and the gene encoding another lymphocyte-specific CC chemokine, EBI1-ligand chemokine (ELC), form a mini-cluster at human chromosome 9p13. Here, we show that SLC is a high affinity functional ligand for chemokine receptor 7 (CCR7) that is expressed on T and B lymphocytes and a known receptor for ELC. SLC induced a vigorous calcium mobilization in murine L1.2 cells stably expressing human CCR7. SLC tagged with the secreted form of alkaline phosphatase (SLC-SEAP) showed specific binding to CCR7 that was fully competed by SLC with an IC50 of 0.5 nM. SLC also induced a vigorous chemotactic response in CCR7-expressing L1.2 cells with a typical bell-shaped dose-response curve and a maximal migration at 10 nM. When assessed using CCR7-transfected L1.2 cells, SLC and ELC were essentially equivalent in terms of cross desensitization in calcium mobilization via CCR7, cross-competition in binding to CCR7, and induction of chemotaxis via CCR7. SLC and ELC were also shown to fully share receptors expressed on cultured normal T cells known to express CCR7. Notably, however, SLC was somehow less efficient in cross-desensitization against ELC in calcium mobilization and in cross-competition with ELC for binding when assessed using cultured normal T cells. Thus, SLC and ELC, even though sharing only 32% amino acid identity, constitute a genetically and functionally highly related subgroup of CC chemokines.
J. Immunol. 174, 4070-4080 (2005)[PubMed:15778365]
CCR7 is necessary to direct dendritic cells (DCs) to secondary lymphoid nodes and to elicit an adaptative immune response. Despite its importance, little is known about the molecular mechanisms used by CCR7 to direct DCs to lymph nodes. In addition to chemotaxis, CCR7 regulates the migratory speed of DCs. We investigated the intracellular pathways that regulate CCR7-dependent chemotaxis and migratory speed. We found that CCR7 induced a G(i)-dependent activation of MAPK members ERK1/2, JNK, and p38, with ERK1/2 and p38 controlling JNK. MAPK members regulated chemotaxis, but not the migratory speed, of DCs. CCR7 induced activation of PI3K/Akt; however, these enzymes did not regulate either chemotaxis or the speed of DCs. CCR7 also induced activation of the GTPase Rho, the tyrosine kinase Pyk2, and inactivation of cofilin. Pyk2 activation was independent of G(i) and Src and was dependent on Rho. Interference with Rho or Pyk2 inhibited cofilin inactivation and the migratory speed of DCs, but did not affect chemotaxis. Interference with Rho/Pyk2/cofilin inhibited DC migratory speed even in the absence of chemokines, suggesting that this module controls the speed of DCs and that CCR7, by activating its components, induces an increase in migratory speed. Therefore, CCR7 activates two independent signaling modules, one involving G(i) and a hierarchy of MAPK family members and another involving Rho/Pyk2/cofilin, which control, respectively, chemotaxis and the migratory speed of DCs. The use of independent signaling modules to control chemotaxis and speed can contribute to regulate the chemotactic effects of CCR7.
J. Biol. Chem. 272, 13803-13809 (1997)[PubMed:9153236]
By searching the expressed sequence tag (EST) data base, we identified partial cDNA sequences encoding a novel human CC chemokine. We determined the complete cDNA sequence that encodes a highly basic polypeptide of a total 98 amino acids with 20 to 30% identity to other human CC chemokines. We termed this novel chemokine from EBI1-Ligand Chemokine as ELC (see below). The ELC mRNA was most strongly expressed in the thymus and lymph nodes. Recombinant ELC protein was expressed as a fusion protein with the Flag tag (ELC-Flag). For receptor-binding assays, recombinant ELC protein fused with the secreted form of alkaline phosphatase (SEAP) was used. By stably expressing five CC chemokine receptors (CCR1 to 5) and five orphan receptors, ELC-SEAP was found to bind specifically to an orphan receptor EBI1. Only ELC-Flag, but not MCP-1, MCP-2, MCP-3, eotaxin, MIP-1alpha, MIP-1beta, RANTES (regulated on activation normal T cell expressed and secreted), thymus and activation-regulated chemokine (TARC), or liver and activation-regulated chemokine (LARC), competed with ELC-SEAP for EBI1. ELC-Flag-induced transient calcium mobilization and chemotactic responses in EBI1-transfected cells. ELC-Flag also induced chemotaxis in HUT78 cells expressing endogenous EBI1 at high levels. By somatic hybrid and radiation hybrid analyses, the gene for ELC (SCYA19) was mapped to chromosome 9p13 instead of chromosome 17q11.2 where the genes for CC chemokines are clustered. Taken together, ELC is a highly specific ligand for EBI1, which is known to be expressed in activated B and T lymphocytes and strongly up-regulated in B cells infected with Epstein-Barr virus and T cells infected with herpesvirus 6 or 7. ELC and EBI1 may thus play roles in migration and homing of normal lymphocytes, as well as in pathophysiology of lymphocytes infected with these herpesviruses. We propose EBI1 to be designated as CCR7.
The directed orientation of T cell signaling molecules and associated membrane rafts towards a chemokine gradient or a contact point with antigen presenting cell.
We studied the role of Rho kinase and extracellular signal-regulated kinase (ERK)-2 in the polarization and migration of T lymphocytes in response to the CCR7 ligands EBI1 ligand chemokine (ELC; CCL19) and secondary lymphoid-tissue chemokine (SLC; CCL21). Both Rho kinase protein isoforms are expressed in T lymphocytes. Inhibition of the Rho kinases with Y-27632 strongly inhibited SLC- and ELC-induced polarized morphology and chemotaxis of T lymphocytes. Although the chemokines induced ERK-2 activation, the blockade of this signaling pathway showed no effect on polarization and migration. This study indicates an important role of Rho kinase in CCR7-mediated polarization and migration of T lymphocytes, whereas ERK-2 is not involved in these processes.
A series of molecular signals that proceeds with an activated receptor promoting the exchange of GDP for GTP on the alpha-subunit of an associated heterotrimeric G-protein complex. The GTP-bound activated alpha-G-protein then dissociates from the beta- and gamma-subunits to further transmit the signal within the cell. The pathway begins with receptor-ligand interaction, or for basal GPCR signaling the pathway begins with the receptor activating its G protein in the absence of an agonist, and ends with regulation of a downstream cellular process, e.g. transcription.
J. Immunol. 176, 5153-5159 (2006)[PubMed:16621978]
CCR7 was described initially as a potent leukocyte chemotactic receptor that was later shown to be responsible of directing the migration of dendritic cells (DCs) to the lymph nodes where these cells play an important role in the initiation of the immune response. Recently, a variety of reports have indicated that, apart from chemotaxis, CCR7 controls the cytoarchitecture, the rate of endocytosis, the survival, the migratory speed, and the maturation of the DCs. Some of these functions of CCR7 and additional ones also have been described in other cell types. Herein we discuss how this receptor may contribute to modulate the immune response by regulating different functions in DCs. Finally, we also suggest a possible mechanism whereby CCR7 may control its multiple tasks in these cells.
The immediate defensive reaction (by vertebrate tissue) to infection or injury caused by chemical or physical agents. The process is characterized by local vasodilation, extravasation of plasma into intercellular spaces and accumulation of white blood cells and macrophages.
The control of dendritic cell (DC) migration is pivotal for the initiation of cellular immune responses. When activated with inflammatory stimuli, the chemokine receptor CCR7 is up-regulated on DCs. Activated DCs home to lymphoid organs, where the CCR7 ligands CCL19 and CCL21 are expressed. We previously found that human monocyte-derived DCs (MoDCs) exclusively migrated to CCL19 and CCL21 when matured in the presence of prostaglandin (PG) E2. Because PGE2 did not alter CCR7 cell surface expression, we examined whether PGE2 may exert its effect by coupling CCR7 to signal transduction modules. Indeed, stimulation with CCR7 ligands led to enhanced phosphatidylinositol-3-kinase-mediated phosphorylation of protein kinase B when MoDCs were matured in the presence of PGE2. Moreover, CCL19/CCL21-induced intracellular calcium mobilization in MoDCs occurred only when PGE2 was present during maturation. MoDC migration to CCL19 and CCL21 was dependent on phospholipase C and intracellular calcium flux but not on phosphatidylinositol-3 kinase. Hence, our data provide insight into CCL19/CCL21-triggered signal transduction pathways and identify a novel function for PGE2 in controlling the migration of mature MoDCs by facilitating CCR7 signal transduction.
The movement of a lymphocyte within the lymphatic system into a lymph node, and its subsequent positioning within defined functional compartments such as sites of cell activation by antigen.
A key feature of the immune system is its ability to induce protective immunity against pathogens while maintaining tolerance towards self and innocuous environmental antigens. Recent evidence suggests that by guiding cells to and within lymphoid organs, CC-chemokine receptor 7 (CCR7) essentially contributes to both immunity and tolerance. This receptor is involved in organizing thymic architecture and function, lymph-node homing of naive and regulatory T cells via high endothelial venules, as well as steady state and inflammation-induced lymph-node-bound migration of dendritic cells via afferent lymphatics. Here, we focus on the cellular and molecular mechanisms that enable CCR7 and its two ligands, CCL19 and CCL21, to balance immunity and tolerance.
The process in which antigen-activated dendritic cells acquire the specialized features of a mature dendritic cell. Mature dendritic cells upregulate the surface expression of MHC molecules, chemokine receptors and adhesion molecules, and increase the number of dendrites (cytoplasmic protrusions) in preparation for migration to lymphoid organs where they present antigen to T cells.
The control of dendritic cell (DC) migration is pivotal for the initiation of cellular immune responses. When activated with inflammatory stimuli, the chemokine receptor CCR7 is up-regulated on DCs. Activated DCs home to lymphoid organs, where the CCR7 ligands CCL19 and CCL21 are expressed. We previously found that human monocyte-derived DCs (MoDCs) exclusively migrated to CCL19 and CCL21 when matured in the presence of prostaglandin (PG) E2. Because PGE2 did not alter CCR7 cell surface expression, we examined whether PGE2 may exert its effect by coupling CCR7 to signal transduction modules. Indeed, stimulation with CCR7 ligands led to enhanced phosphatidylinositol-3-kinase-mediated phosphorylation of protein kinase B when MoDCs were matured in the presence of PGE2. Moreover, CCL19/CCL21-induced intracellular calcium mobilization in MoDCs occurred only when PGE2 was present during maturation. MoDC migration to CCL19 and CCL21 was dependent on phospholipase C and intracellular calcium flux but not on phosphatidylinositol-3 kinase. Hence, our data provide insight into CCL19/CCL21-triggered signal transduction pathways and identify a novel function for PGE2 in controlling the migration of mature MoDCs by facilitating CCR7 signal transduction.
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.
Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1alpha and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.
BACKGROUND: Adherence of human mesangial cells to the surrounding matrix contributes to glomerular homeostasis and is important for the maintenance of glomerular architecture and function in normal adult human kidney. The expression of chemokines and corresponding chemokine receptors on adjacent intrinsic renal cells indicates a novel chemokine/chemokine receptor function on nonimmune cells important for glomerular homeostasis. A constitutive expression of the chemokine SLC/CCL21 on human podocytes and of its corresponding receptor CCR7 on mesangial cells was shown before. SLC/CCL21 has a positive effect on proliferation and migration of mesangial cells and leads to increased cell survival in Fas-induced apoptosis. In leukocytes chemokines mediate integrin-dependent firm adhesion. Therefore, we examined the influence of chemokine receptor CCR7 activation by SLC/CCL21 on adhesive properties of human mesangial cells to matrix molecules. METHODS: Adhesion assays, mechanical detachment assays, and evaluation of integrin activation by integrin-linked kinase activity were performed. Changes in the cytoskeletal F-actin were illustrated by phalloidin immunofluorescence staining. RESULTS: SLC/CCL21 stimulation enhanced adhesiveness to fibronectin in a time- and concentration-dependent manner. SLC/CCL21 also increased the firmness of mesangial cells adhesion as judged by detachment assays. Furthermore activation of integrin-linked kinase occurred with SLC/CCL21 addition to mesangial cells, resulting in increased phosphorylation of glycogen synthase kinase-3 (GSK-3) and protein kinase B (PKB/Akt). Exposure of mesangial cells to SLC/CCL21 also resulted in F-actin rearrangements with membrane ruffling and extensions leading to bridging between mesangial cells. CONCLUSION: Activation of CCR7 on mesangial cells by SLC/CCL21 enhances the degree and firmness of cell adhesion and increases cell spreading and the formation of cell-cell contacts. This includes integrin-linked kinase activation and F-actin rearrangements. Thus, local chemokine generation and chemokine receptor expression on mesangial cells may play an important role in the maintenance of glomerular homeostasis and in local remodeling processes.
J. Immunol. 174, 4070-4080 (2005)[PubMed:15778365]
CCR7 is necessary to direct dendritic cells (DCs) to secondary lymphoid nodes and to elicit an adaptative immune response. Despite its importance, little is known about the molecular mechanisms used by CCR7 to direct DCs to lymph nodes. In addition to chemotaxis, CCR7 regulates the migratory speed of DCs. We investigated the intracellular pathways that regulate CCR7-dependent chemotaxis and migratory speed. We found that CCR7 induced a G(i)-dependent activation of MAPK members ERK1/2, JNK, and p38, with ERK1/2 and p38 controlling JNK. MAPK members regulated chemotaxis, but not the migratory speed, of DCs. CCR7 induced activation of PI3K/Akt; however, these enzymes did not regulate either chemotaxis or the speed of DCs. CCR7 also induced activation of the GTPase Rho, the tyrosine kinase Pyk2, and inactivation of cofilin. Pyk2 activation was independent of G(i) and Src and was dependent on Rho. Interference with Rho or Pyk2 inhibited cofilin inactivation and the migratory speed of DCs, but did not affect chemotaxis. Interference with Rho/Pyk2/cofilin inhibited DC migratory speed even in the absence of chemokines, suggesting that this module controls the speed of DCs and that CCR7, by activating its components, induces an increase in migratory speed. Therefore, CCR7 activates two independent signaling modules, one involving G(i) and a hierarchy of MAPK family members and another involving Rho/Pyk2/cofilin, which control, respectively, chemotaxis and the migratory speed of DCs. The use of independent signaling modules to control chemotaxis and speed can contribute to regulate the chemotactic effects of CCR7.
BACKGROUND: Adherence of human mesangial cells to the surrounding matrix contributes to glomerular homeostasis and is important for the maintenance of glomerular architecture and function in normal adult human kidney. The expression of chemokines and corresponding chemokine receptors on adjacent intrinsic renal cells indicates a novel chemokine/chemokine receptor function on nonimmune cells important for glomerular homeostasis. A constitutive expression of the chemokine SLC/CCL21 on human podocytes and of its corresponding receptor CCR7 on mesangial cells was shown before. SLC/CCL21 has a positive effect on proliferation and migration of mesangial cells and leads to increased cell survival in Fas-induced apoptosis. In leukocytes chemokines mediate integrin-dependent firm adhesion. Therefore, we examined the influence of chemokine receptor CCR7 activation by SLC/CCL21 on adhesive properties of human mesangial cells to matrix molecules. METHODS: Adhesion assays, mechanical detachment assays, and evaluation of integrin activation by integrin-linked kinase activity were performed. Changes in the cytoskeletal F-actin were illustrated by phalloidin immunofluorescence staining. RESULTS: SLC/CCL21 stimulation enhanced adhesiveness to fibronectin in a time- and concentration-dependent manner. SLC/CCL21 also increased the firmness of mesangial cells adhesion as judged by detachment assays. Furthermore activation of integrin-linked kinase occurred with SLC/CCL21 addition to mesangial cells, resulting in increased phosphorylation of glycogen synthase kinase-3 (GSK-3) and protein kinase B (PKB/Akt). Exposure of mesangial cells to SLC/CCL21 also resulted in F-actin rearrangements with membrane ruffling and extensions leading to bridging between mesangial cells. CONCLUSION: Activation of CCR7 on mesangial cells by SLC/CCL21 enhances the degree and firmness of cell adhesion and increases cell spreading and the formation of cell-cell contacts. This includes integrin-linked kinase activation and F-actin rearrangements. Thus, local chemokine generation and chemokine receptor expression on mesangial cells may play an important role in the maintenance of glomerular homeostasis and in local remodeling processes.
We studied the role of Rho kinase and extracellular signal-regulated kinase (ERK)-2 in the polarization and migration of T lymphocytes in response to the CCR7 ligands EBI1 ligand chemokine (ELC; CCL19) and secondary lymphoid-tissue chemokine (SLC; CCL21). Both Rho kinase protein isoforms are expressed in T lymphocytes. Inhibition of the Rho kinases with Y-27632 strongly inhibited SLC- and ELC-induced polarized morphology and chemotaxis of T lymphocytes. Although the chemokines induced ERK-2 activation, the blockade of this signaling pathway showed no effect on polarization and migration. This study indicates an important role of Rho kinase in CCR7-mediated polarization and migration of T lymphocytes, whereas ERK-2 is not involved in these processes.
J. Immunol. 174, 4070-4080 (2005)[PubMed:15778365]
CCR7 is necessary to direct dendritic cells (DCs) to secondary lymphoid nodes and to elicit an adaptative immune response. Despite its importance, little is known about the molecular mechanisms used by CCR7 to direct DCs to lymph nodes. In addition to chemotaxis, CCR7 regulates the migratory speed of DCs. We investigated the intracellular pathways that regulate CCR7-dependent chemotaxis and migratory speed. We found that CCR7 induced a G(i)-dependent activation of MAPK members ERK1/2, JNK, and p38, with ERK1/2 and p38 controlling JNK. MAPK members regulated chemotaxis, but not the migratory speed, of DCs. CCR7 induced activation of PI3K/Akt; however, these enzymes did not regulate either chemotaxis or the speed of DCs. CCR7 also induced activation of the GTPase Rho, the tyrosine kinase Pyk2, and inactivation of cofilin. Pyk2 activation was independent of G(i) and Src and was dependent on Rho. Interference with Rho or Pyk2 inhibited cofilin inactivation and the migratory speed of DCs, but did not affect chemotaxis. Interference with Rho/Pyk2/cofilin inhibited DC migratory speed even in the absence of chemokines, suggesting that this module controls the speed of DCs and that CCR7, by activating its components, induces an increase in migratory speed. Therefore, CCR7 activates two independent signaling modules, one involving G(i) and a hierarchy of MAPK family members and another involving Rho/Pyk2/cofilin, which control, respectively, chemotaxis and the migratory speed of DCs. The use of independent signaling modules to control chemotaxis and speed can contribute to regulate the chemotactic effects of CCR7.
Any process that activates or increases the frequency, rate or extent of the assembly of a filopodium, a thin, stiff protrusion extended by the leading edge of a motile cell such as a crawling fibroblast or amoeba, or an axonal growth cone.
BACKGROUND: Adherence of human mesangial cells to the surrounding matrix contributes to glomerular homeostasis and is important for the maintenance of glomerular architecture and function in normal adult human kidney. The expression of chemokines and corresponding chemokine receptors on adjacent intrinsic renal cells indicates a novel chemokine/chemokine receptor function on nonimmune cells important for glomerular homeostasis. A constitutive expression of the chemokine SLC/CCL21 on human podocytes and of its corresponding receptor CCR7 on mesangial cells was shown before. SLC/CCL21 has a positive effect on proliferation and migration of mesangial cells and leads to increased cell survival in Fas-induced apoptosis. In leukocytes chemokines mediate integrin-dependent firm adhesion. Therefore, we examined the influence of chemokine receptor CCR7 activation by SLC/CCL21 on adhesive properties of human mesangial cells to matrix molecules. METHODS: Adhesion assays, mechanical detachment assays, and evaluation of integrin activation by integrin-linked kinase activity were performed. Changes in the cytoskeletal F-actin were illustrated by phalloidin immunofluorescence staining. RESULTS: SLC/CCL21 stimulation enhanced adhesiveness to fibronectin in a time- and concentration-dependent manner. SLC/CCL21 also increased the firmness of mesangial cells adhesion as judged by detachment assays. Furthermore activation of integrin-linked kinase occurred with SLC/CCL21 addition to mesangial cells, resulting in increased phosphorylation of glycogen synthase kinase-3 (GSK-3) and protein kinase B (PKB/Akt). Exposure of mesangial cells to SLC/CCL21 also resulted in F-actin rearrangements with membrane ruffling and extensions leading to bridging between mesangial cells. CONCLUSION: Activation of CCR7 on mesangial cells by SLC/CCL21 enhances the degree and firmness of cell adhesion and increases cell spreading and the formation of cell-cell contacts. This includes integrin-linked kinase activation and F-actin rearrangements. Thus, local chemokine generation and chemokine receptor expression on mesangial cells may play an important role in the maintenance of glomerular homeostasis and in local remodeling processes.
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.
J. Immunol. 174, 4070-4080 (2005)[PubMed:15778365]
CCR7 is necessary to direct dendritic cells (DCs) to secondary lymphoid nodes and to elicit an adaptative immune response. Despite its importance, little is known about the molecular mechanisms used by CCR7 to direct DCs to lymph nodes. In addition to chemotaxis, CCR7 regulates the migratory speed of DCs. We investigated the intracellular pathways that regulate CCR7-dependent chemotaxis and migratory speed. We found that CCR7 induced a G(i)-dependent activation of MAPK members ERK1/2, JNK, and p38, with ERK1/2 and p38 controlling JNK. MAPK members regulated chemotaxis, but not the migratory speed, of DCs. CCR7 induced activation of PI3K/Akt; however, these enzymes did not regulate either chemotaxis or the speed of DCs. CCR7 also induced activation of the GTPase Rho, the tyrosine kinase Pyk2, and inactivation of cofilin. Pyk2 activation was independent of G(i) and Src and was dependent on Rho. Interference with Rho or Pyk2 inhibited cofilin inactivation and the migratory speed of DCs, but did not affect chemotaxis. Interference with Rho/Pyk2/cofilin inhibited DC migratory speed even in the absence of chemokines, suggesting that this module controls the speed of DCs and that CCR7, by activating its components, induces an increase in migratory speed. Therefore, CCR7 activates two independent signaling modules, one involving G(i) and a hierarchy of MAPK family members and another involving Rho/Pyk2/cofilin, which control, respectively, chemotaxis and the migratory speed of DCs. The use of independent signaling modules to control chemotaxis and speed can contribute to regulate the chemotactic effects of CCR7.
Any process that increases the frequency, rate, or extent of neutrophil chemotaxis. Neutrophil chemotaxis is the directed movement of a neutrophil cell, the most numerous polymorphonuclear leukocyte found in the blood, in response to an external stimulus, usually an infection or wounding.
Increasing evidence suggests that neutrophils may participate in the regulation of adaptive immune responses, and can reach draining lymph nodes and cross-prime naive T cells. The aim of this study was to identify the mechanism(s) involved in the migration of neutrophils to the draining lymph nodes. We demonstrate that a subpopulation of human and mouse neutrophils express CCR7. CCR7 is rapidly expressed at the membrane upon stimulation. In vitro, stimulated human neutrophils migrate in response to the CCR7 ligands CCL19 and CCL21. In vivo, injection of complete Freund adjuvant induces a rapid recruitment of neutrophils to the lymph nodes in wild-type mice but not in Ccr7(-/-) mice. Moreover, intradermally injected interleukin-17-and granulocyte-macrophage colony-stimulating factor-stimulated neutrophils from wild-type mice, but not from Ccr7(-/-) mice, migrate to the draining lymph nodes. These results identify CCR7 as a chemokine receptor involved in the migration of neutrophils to the lymph nodes.
J. Immunol. 174, 4070-4080 (2005)[PubMed:15778365]
CCR7 is necessary to direct dendritic cells (DCs) to secondary lymphoid nodes and to elicit an adaptative immune response. Despite its importance, little is known about the molecular mechanisms used by CCR7 to direct DCs to lymph nodes. In addition to chemotaxis, CCR7 regulates the migratory speed of DCs. We investigated the intracellular pathways that regulate CCR7-dependent chemotaxis and migratory speed. We found that CCR7 induced a G(i)-dependent activation of MAPK members ERK1/2, JNK, and p38, with ERK1/2 and p38 controlling JNK. MAPK members regulated chemotaxis, but not the migratory speed, of DCs. CCR7 induced activation of PI3K/Akt; however, these enzymes did not regulate either chemotaxis or the speed of DCs. CCR7 also induced activation of the GTPase Rho, the tyrosine kinase Pyk2, and inactivation of cofilin. Pyk2 activation was independent of G(i) and Src and was dependent on Rho. Interference with Rho or Pyk2 inhibited cofilin inactivation and the migratory speed of DCs, but did not affect chemotaxis. Interference with Rho/Pyk2/cofilin inhibited DC migratory speed even in the absence of chemokines, suggesting that this module controls the speed of DCs and that CCR7, by activating its components, induces an increase in migratory speed. Therefore, CCR7 activates two independent signaling modules, one involving G(i) and a hierarchy of MAPK family members and another involving Rho/Pyk2/cofilin, which control, respectively, chemotaxis and the migratory speed of DCs. The use of independent signaling modules to control chemotaxis and speed can contribute to regulate the chemotactic effects of CCR7.
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.
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.
The control of dendritic cell (DC) migration is pivotal for the initiation of cellular immune responses. When activated with inflammatory stimuli, the chemokine receptor CCR7 is up-regulated on DCs. Activated DCs home to lymphoid organs, where the CCR7 ligands CCL19 and CCL21 are expressed. We previously found that human monocyte-derived DCs (MoDCs) exclusively migrated to CCL19 and CCL21 when matured in the presence of prostaglandin (PG) E2. Because PGE2 did not alter CCR7 cell surface expression, we examined whether PGE2 may exert its effect by coupling CCR7 to signal transduction modules. Indeed, stimulation with CCR7 ligands led to enhanced phosphatidylinositol-3-kinase-mediated phosphorylation of protein kinase B when MoDCs were matured in the presence of PGE2. Moreover, CCL19/CCL21-induced intracellular calcium mobilization in MoDCs occurred only when PGE2 was present during maturation. MoDC migration to CCL19 and CCL21 was dependent on phospholipase C and intracellular calcium flux but not on phosphatidylinositol-3 kinase. Hence, our data provide insight into CCL19/CCL21-triggered signal transduction pathways and identify a novel function for PGE2 in controlling the migration of mature MoDCs by facilitating CCR7 signal transduction.
Any process that activates or increases the frequency, rate or extent of the protein kinase B signaling cascade, a series of reactions mediated by the intracellular serine/threonine kinase protein kinase B.
J. Immunol. 174, 4070-4080 (2005)[PubMed:15778365]
CCR7 is necessary to direct dendritic cells (DCs) to secondary lymphoid nodes and to elicit an adaptative immune response. Despite its importance, little is known about the molecular mechanisms used by CCR7 to direct DCs to lymph nodes. In addition to chemotaxis, CCR7 regulates the migratory speed of DCs. We investigated the intracellular pathways that regulate CCR7-dependent chemotaxis and migratory speed. We found that CCR7 induced a G(i)-dependent activation of MAPK members ERK1/2, JNK, and p38, with ERK1/2 and p38 controlling JNK. MAPK members regulated chemotaxis, but not the migratory speed, of DCs. CCR7 induced activation of PI3K/Akt; however, these enzymes did not regulate either chemotaxis or the speed of DCs. CCR7 also induced activation of the GTPase Rho, the tyrosine kinase Pyk2, and inactivation of cofilin. Pyk2 activation was independent of G(i) and Src and was dependent on Rho. Interference with Rho or Pyk2 inhibited cofilin inactivation and the migratory speed of DCs, but did not affect chemotaxis. Interference with Rho/Pyk2/cofilin inhibited DC migratory speed even in the absence of chemokines, suggesting that this module controls the speed of DCs and that CCR7, by activating its components, induces an increase in migratory speed. Therefore, CCR7 activates two independent signaling modules, one involving G(i) and a hierarchy of MAPK family members and another involving Rho/Pyk2/cofilin, which control, respectively, chemotaxis and the migratory speed of DCs. The use of independent signaling modules to control chemotaxis and speed can contribute to regulate the chemotactic effects of CCR7.
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.
Breast cancer is characterized by a distinct metastatic pattern involving the regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which is critically regulated by chemokines and their receptors. Here we report that the chemokine receptors CXCR4 and CCR7 are highly expressed in human breast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1alpha and CCL21/6Ckine exhibit peak levels of expression in organs representing the first destinations of breast cancer metastasis. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemotactic and invasive responses. In vivo, neutralizing the interactions of CXCL12/CXCR4 significantly impairs metastasis of breast cancer cells to regional lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, shows high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findings indicate that chemokines and their receptors have a critical role in determining the metastatic destination of tumour cells.
Any process that activates or increases the frequency, rate or extent of signaling pathways initiated by the cross-linking of an antigen receptor on a T cell.
The process in which calcium ions sequestered in the endoplasmic reticulum, Golgi apparatus or mitochondria are released into the cytosolic compartment.
The control of dendritic cell (DC) migration is pivotal for the initiation of cellular immune responses. When activated with inflammatory stimuli, the chemokine receptor CCR7 is up-regulated on DCs. Activated DCs home to lymphoid organs, where the CCR7 ligands CCL19 and CCL21 are expressed. We previously found that human monocyte-derived DCs (MoDCs) exclusively migrated to CCL19 and CCL21 when matured in the presence of prostaglandin (PG) E2. Because PGE2 did not alter CCR7 cell surface expression, we examined whether PGE2 may exert its effect by coupling CCR7 to signal transduction modules. Indeed, stimulation with CCR7 ligands led to enhanced phosphatidylinositol-3-kinase-mediated phosphorylation of protein kinase B when MoDCs were matured in the presence of PGE2. Moreover, CCL19/CCL21-induced intracellular calcium mobilization in MoDCs occurred only when PGE2 was present during maturation. MoDC migration to CCL19 and CCL21 was dependent on phospholipase C and intracellular calcium flux but not on phosphatidylinositol-3 kinase. Hence, our data provide insight into CCL19/CCL21-triggered signal transduction pathways and identify a novel function for PGE2 in controlling the migration of mature MoDCs by facilitating CCR7 signal transduction.
Any process that results in a change in state or activity of an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a lipopolysaccharide stimulus; lipopolysaccharide is a major component of the cell wall of gram-negative bacteria.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a nitric oxide stimulus.
Dendritic-cell (DC) migration to secondary lymphoid organs is crucial for the initiation of adaptive immune responses. Although LPS up-regulates CCR7 on DCs, a second signal is required to enable them to migrate toward the chemokine CCL19 (MIP-3beta). We found that the nitric oxide (NO) donor NOR4 provides a signal allowing LPS-stimulated DCs to migrate toward CCL19. NO affects DC migration through both the initial activation of the cGMP/cGMP kinase (cGMP/cGK) pathway and a long-term effect that reduced cGK activity via negative feedback. Indeed, migration of DCs toward CCL19, unlike migration toward CXCL12 (SDF-1alpha), required inhibition of cGK. LPS increased both cGK expression and cGK activity as measured by phosphorylation of the key cGK target vasodilator-stimulated phosphoprotein (VASP). Because cGK phosphorylation of VASP can disrupt focal adhesions and inhibit cell migration, LPS-induced VASP phosphorylation may prevent DCs from migrating without a second signal. Long-term NOR4 treatment inhibited the increase in cGK-dependent VASP phosphorylation, releasing this brake so that DCs can migrate. NO has been implicated in the regulation of autoimmunity through its effect on T cells. Our results suggest that NO regulation of DC migration and cytokine production may contribute to the protective effects of NO in autoimmune disorders.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a prostagladin E stimulus.
The control of dendritic cell (DC) migration is pivotal for the initiation of cellular immune responses. When activated with inflammatory stimuli, the chemokine receptor CCR7 is up-regulated on DCs. Activated DCs home to lymphoid organs, where the CCR7 ligands CCL19 and CCL21 are expressed. We previously found that human monocyte-derived DCs (MoDCs) exclusively migrated to CCL19 and CCL21 when matured in the presence of prostaglandin (PG) E2. Because PGE2 did not alter CCR7 cell surface expression, we examined whether PGE2 may exert its effect by coupling CCR7 to signal transduction modules. Indeed, stimulation with CCR7 ligands led to enhanced phosphatidylinositol-3-kinase-mediated phosphorylation of protein kinase B when MoDCs were matured in the presence of PGE2. Moreover, CCL19/CCL21-induced intracellular calcium mobilization in MoDCs occurred only when PGE2 was present during maturation. MoDC migration to CCL19 and CCL21 was dependent on phospholipase C and intracellular calcium flux but not on phosphatidylinositol-3 kinase. Hence, our data provide insight into CCL19/CCL21-triggered signal transduction pathways and identify a novel function for PGE2 in controlling the migration of mature MoDCs by facilitating CCR7 signal transduction.
A process that is carried out at the cellular level which results in the assembly, arrangement of constituent parts, or disassembly of a ruffle, a projection at the leading edge of a crawling cell.
BACKGROUND: Adherence of human mesangial cells to the surrounding matrix contributes to glomerular homeostasis and is important for the maintenance of glomerular architecture and function in normal adult human kidney. The expression of chemokines and corresponding chemokine receptors on adjacent intrinsic renal cells indicates a novel chemokine/chemokine receptor function on nonimmune cells important for glomerular homeostasis. A constitutive expression of the chemokine SLC/CCL21 on human podocytes and of its corresponding receptor CCR7 on mesangial cells was shown before. SLC/CCL21 has a positive effect on proliferation and migration of mesangial cells and leads to increased cell survival in Fas-induced apoptosis. In leukocytes chemokines mediate integrin-dependent firm adhesion. Therefore, we examined the influence of chemokine receptor CCR7 activation by SLC/CCL21 on adhesive properties of human mesangial cells to matrix molecules. METHODS: Adhesion assays, mechanical detachment assays, and evaluation of integrin activation by integrin-linked kinase activity were performed. Changes in the cytoskeletal F-actin were illustrated by phalloidin immunofluorescence staining. RESULTS: SLC/CCL21 stimulation enhanced adhesiveness to fibronectin in a time- and concentration-dependent manner. SLC/CCL21 also increased the firmness of mesangial cells adhesion as judged by detachment assays. Furthermore activation of integrin-linked kinase occurred with SLC/CCL21 addition to mesangial cells, resulting in increased phosphorylation of glycogen synthase kinase-3 (GSK-3) and protein kinase B (PKB/Akt). Exposure of mesangial cells to SLC/CCL21 also resulted in F-actin rearrangements with membrane ruffling and extensions leading to bridging between mesangial cells. CONCLUSION: Activation of CCR7 on mesangial cells by SLC/CCL21 enhances the degree and firmness of cell adhesion and increases cell spreading and the formation of cell-cell contacts. This includes integrin-linked kinase activation and F-actin rearrangements. Thus, local chemokine generation and chemokine receptor expression on mesangial cells may play an important role in the maintenance of glomerular homeostasis and in local remodeling processes.
Receptors which transduce extracellular signals across the cell membrane. At the external side they receive a ligand (a photon in case of opsins), and at the cytosolic side they activate a guanine nucleotide-binding (G) protein. These receptors are hydrophobic proteins that cross the membrane seven times.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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