-
Acta Ophthalmologica Feb 2019To determine the concentrations of the CC chemokines CCL2, CCL7, CCL8, CCL11, CCL13, CCL20, CCL24 and CCL26 in aqueous humour (AH) samples from patients with specific...
PURPOSE
To determine the concentrations of the CC chemokines CCL2, CCL7, CCL8, CCL11, CCL13, CCL20, CCL24 and CCL26 in aqueous humour (AH) samples from patients with specific uveitic entities.
METHODS
Aqueous humour samples from patients with active uveitis associated with Behçet's disease (BD) (n = 13), sarcoidosis (n = 8), HLA-B27-related inflammation (n = 12), Vogt-Koyanagi-Harada (VKH) disease (n = 12) and control patients (n = 9) were assayed with the use of a multiplex assay.
RESULTS
When considering all uveitis patients as one group, all chemokine levels except CCL2 were significantly increased compared to controls. CCL8, CCL13 and CCL20 were the most strongly upregulated, 48-fold, 118-fold and 173-fold, respectively, above control AH levels. CCL8 and CCL13 levels were significantly higher in HLA-B27-associated uveitis than in sarcoidosis and VKH disease. CCL20 levels were significantly higher in HLA-B27-associated uveitis than in BD, sarcoidosis and VKH disease. In addition, CCL20 levels were significantly higher in BD than in VKH disease. In HLA-B27-associated uveitis, CCL8, CCL13 and CCL20 were upregulated 111-fold, 255-fold and 465-fold, respectively, compared with controls. CCL8, CCL13 and CCL20 levels were significantly higher in nongranulomatous uveitis (BD and HLA-B27-associated uveitis) than in granulomatous uveitis (sarcoidosis and VKH disease).
CONCLUSION
Immune responses mediated by CCL8, CCL13 and CCL20 appear to be more potent in nongranulomatous uveitis, particularly in HLA-B27-associated uveitis.
Topics: Aqueous Humor; Biomarkers; Chemokine CCL20; Chemokine CCL8; Chemokines, CC; Fluorescein Angiography; Fundus Oculi; HLA-B27 Antigen; Humans; Monocyte Chemoattractant Proteins; Ophthalmoscopy; Uveitis
PubMed: 30242977
DOI: 10.1111/aos.13835 -
European Cytokine Network 2001We investigated the effect of IFN-beta on beta-chemokine expression in differentiating human peripheral blood monocytes. MCP-1, MIP-1alpha and MIP-1beta were...
We investigated the effect of IFN-beta on beta-chemokine expression in differentiating human peripheral blood monocytes. MCP-1, MIP-1alpha and MIP-1beta were constitutively expressed in 1 day-cultured monocytes, and their secretion increased with time in culture despite any change in mRNA accumulation. IFN-beta treatment of differentiating monocytes resulted in a marked and dose-dependent increase of beta-chemokine secretion, which was regulated differently with respect to the differentiation stage. In particular, IFN-beta upregulated MCP-1 secretion in monocytes at all stages of differentiation although its effect was significantly higher in 1-day cultured monocytes as compared to monocyte-derived macrophages (MDM). In contrast, MIP-1alpha and MIP-1beta secretion was up-regulated by IFN-beta only in MDM. Although MCP-1, MIP-1alpha and MIP-1beta mRNA expression was up-regulated by IFN-beta in both 1 day-cultured monocytes and MDM, no correlation was found between mRNA level and protein secretion. These results suggest that the regulation of beta-chemokine secretion in monocytes/macrophages by IFN-beta occurred through different mechanisms, involving both a direct effect of this cytokine on chemokine gene expression and translational/post-translational steps of regulation more likely linked to the differentiation process. This finding reveals a novel role for this cytokine in the recruitment of specific cell types during the immune response, which may be relevant in the control of viral infections in vivo.
Topics: Adolescent; Adult; Cell Differentiation; Chemokines, CC; Humans; In Vitro Techniques; Interferon-beta; Macrophages; Male; Monocytes; RNA, Messenger
PubMed: 11781186
DOI: No ID Found -
Immunology Apr 2000A non-cognate mechanism of protection against human immunodeficiency virus-1 (HIV-1) infection involves up-regulation of beta-chemokines, which bind and may...
A non-cognate mechanism of protection against human immunodeficiency virus-1 (HIV-1) infection involves up-regulation of beta-chemokines, which bind and may down-modulate the CCR5 co-receptors, thereby preventing transmission of M-tropic HIV-1. The objective of this investigation was to evaluate this mechanism in vivo in non-human primates. Rhesus macaques were immunized by a modified targeted lymph nodes (TLN) route with recombinant simian immunodeficiency virus (SIV) glycoprotein 120 (gp120) and p27 in alum, and adsorbed recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) with either interleukin (IL)-2 or IL-4. Immunization induced significant increases in the concentrations of CD8 cell-derived suppressor factor (CD8-SF), regulated on activation normal T cells expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1alpha and MIP-1beta, and down-modulation of the proportion of cells expressing CCR5 (r = 0.737, P<0.05). The macaques were then challenged with SIVmac 220 by the rectal mucosal route. The plasma SIVmac RNA showed a significant inverse correlation with the CD8-SF or the concentration of the three beta-chemokines (r = 0.831 and 0.824, P<0.01), but a positive correlation between the proportion of CCR5+ cells and SIVmac RNA (r = 0.613, P = 0.05). These results demonstrate for the first time in vivo that immunization up-regulates beta-chemokines, which may down-modulate CCR5 co-receptors, and both functions are significantly correlated with the viral load. Hence, the non-cognate beta-chemokine-CCR5 mechanism should be considered as complementary to specific immunity in vaccination against HIV.
Topics: Animals; CD8 Antigens; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5; Chemokines, CC; Gene Products, env; Gene Products, gag; Granulocyte-Macrophage Colony-Stimulating Factor; Groin; HIV Envelope Protein gp120; Injections, Subcutaneous; Interleukin-2; Interleukin-4; Macaca mulatta; Macrophage Inflammatory Proteins; Membrane Glycoproteins; Mucous Membrane; RNA; Receptors, CCR5; Recombinant Proteins; Rectum; Retroviridae Proteins, Oncogenic; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Viral Envelope Proteins; Viral Fusion Proteins; Viral Load; Viral Vaccines
PubMed: 10792505
DOI: 10.1046/j.1365-2567.2000.00993.x -
FASEB Journal : Official Publication of... Apr 2020Chemokines and their receptors play important roles in vascular homeostasis, development, and angiogenesis. Little is known regarding the molecular signaling mechanisms...
Chemokines and their receptors play important roles in vascular homeostasis, development, and angiogenesis. Little is known regarding the molecular signaling mechanisms activated by CCL28 chemokine via its primary receptor CCR10 in endothelial cells (ECs). Here, we test the hypothesis that CCL28/CCR10 signaling plays an important role in regulating skin wound angiogenesis through endothelial nitric oxide synthase (eNOS)-dependent Src, PI3K, and MAPK signaling. We observed nitric oxide (NO) production in human primary ECs stimulated with exogenous CCL28, which also induced direct binding of CCR10 and eNOS resulting in inhibition of eNOS activity. Knockdown of CCR10 with siRNA lead to reduced eNOS expression and tube formation suggesting the involvement of CCR10 in EC angiogenesis. Based on this interaction, we engineered a myristoylated 7 amino acid CCR10-binding domain (Myr-CBD7) peptide and showed that this can block eNOS interaction with CCR10, but not with calmodulin, resulting in upregulation of eNOS activity. Importantly, topical administration of Myr-CBD7 peptide on mouse dermal wounds not only blocked CCR10-eNOS interaction, but also enhanced expression of eNOS, CD31, and IL-4 with reduction of CCL28 and IL-6 levels associated with improved wound healing. These results point to a potential therapeutic strategy to upregulate NO bioavailability, enhance angiogenesis, and improve wound healing by disrupting CCL28-activated CCR10-eNOS interaction.
Topics: Animals; Chemokines, CC; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; Receptors, CCR10; Skin; Wound Healing
PubMed: 32124475
DOI: 10.1096/fj.201902060R -
Journal of Leukocyte Biology Jul 2005CC chemokine ligand 18 (CCL18) was originally discovered as pulmonary and activation-regulated chemokine (PARC), dendritic cell (DC)-chemokine 1 (DC-CK1), alternative... (Review)
Review
CC chemokine ligand 18 (CCL18) was originally discovered as pulmonary and activation-regulated chemokine (PARC), dendritic cell (DC)-chemokine 1 (DC-CK1), alternative macrophage activation-associated CC chemokine-1 (AMAC-1), and macrophage inflammatory protein-4 (MIP-4). CCL18 primarily targets lymphocytes and immature DC, although its agonistic receptor remains unknown so far. CCL18 is mainly expressed by a broad range of monocytes/macrophages and DC. A more profound understanding of the various activation programs and functional phenotypes of these producer cells might give a better insight in the proinflammatory versus anti-inflammatory role of this CC chemokine. It is interesting that CCL18 is constitutively present at high levels in human plasma and likely contributes to the physiological homing of lymphocytes and DC and to the generation of primary immune responses. Furthermore, enhanced CCL18 production has been demonstrated in several diseases, including various malignancies and inflammatory joint, lung, and skin diseases. The lack of a rodent counterpart for human CCL18 sets all hope on primate animal models to further elucidate the importance of CCL18 in vivo. This review will address these different aspects in more detail.
Topics: Animals; Autoimmune Diseases; Chemokines, CC; Chemotaxis, Leukocyte; Dendritic Cells; Humans; Inflammation; Inflammation Mediators; Macrophages; Neoplasms; Receptors, Lymphocyte Homing
PubMed: 15784687
DOI: 10.1189/jlb.1204712 -
The Journal of Reproduction and... Feb 2020In bovine placentomes, the inflammatory response is considered important for the detachment of the fetal membrane from the caruncle after parturition. Glucocorticoids, a...
In bovine placentomes, the inflammatory response is considered important for the detachment of the fetal membrane from the caruncle after parturition. Glucocorticoids, a trigger of the onset of parturition, facilitate functional maturation of placentomes via prostaglandin (PG) and estrogen production in cattle. This study investigated how exogeneous glucocorticoids, which exert immunosuppressive effects, affect placental inflammation at parturition. Placentomes were collected immediately after spontaneous or induced parturition. Parturition was conventionally induced using PGF2α or dexamethasone or with a combination of triamcinolone acetonide and high-dose betamethasone (TABET treatment). Polymerase chain reaction (PCR) array analysis indicated that 9/13 C-C motif chemokine ligands (CCLs) were upregulated > two-fold in spontaneous parturition, with CCL2 and CCL8 being highly expressed. The expressions of CCL2, CCL8, C-C motif chemokine receptor 1 (CCR1), and CCR5 in caruncles were significantly higher in spontaneous parturition than in induced parturition. Although the clinical dose of dexamethasone did not influence the expression of these CCLs and CCRs, TABET treatment increased CCR1 expression. CCL8, CCR1, CCR2, and CCR5 were localized in the caruncular epithelial cells. CCR2 was also localized in the epithelial cells of the cotyledonary villi. This study is the first report to reveal the disruption in CCL and CCR expression in bovine placentomes at induced parturition. Enhanced glucocorticoid exposure for the induction of parturition may upregulate CCR1 expression in placentomes, but the treatment does not adequately promote CCL expression. Additionally, immunohistochemistry suggested that the CCL-CCR system is involved in the functional regulation of maternal and fetal epithelial cells in placentomes at parturition.
Topics: Animals; Cattle; Chemokines, CC; Epithelial Cells; Female; Parturition; Placenta; Pregnancy; Receptors, Chemokine
PubMed: 31761882
DOI: 10.1262/jrd.2019-113 -
Clinical and Experimental Immunology Oct 1999Expression of chemokine receptors and beta-chemokine production by peripheral blood mononuclear cells (PBMC) were determined in HIV-1-infected individuals before and...
Expression of chemokine receptors and beta-chemokine production by peripheral blood mononuclear cells (PBMC) were determined in HIV-1-infected individuals before and after highly active anti-retroviral therapy (HAART) and their relationship to viral load, T cell phenotype and the expression of immunological activation markers was examined. We found that the expression of CCR5 is up-regulated in HIV-1-infected individuals while CXCR4 appears down-regulated on both CD4 and CD8 T cells compared with normal controls. These alterations are associated with the high levels of viral load. In addition, a relationship was observed between the degree of immune activation and chemokine receptor expression on T cells. However, after 3 months of combined anti-retroviral regimen, expression of CXCR4 significantly increased while CCR5 decreased when compared with pretherapy determinations. This was seen in strict association with a dramatic decrease of viral load and an increase of both CD45RA+/CD62L+ (naive) and CD45RA-/CD62L+ or CD45RA+/CD62L- (memory) T cells accompanied by a significant decrease of the expression of immune activation markers such as HLA-DR and CD38. At enrolment, both spontaneous and lectin-induced RANTES, macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta production by PBMC were higher in HIV-1-infected individuals compared with normal controls, although differences for MIP-1beta were not statistically significant. However, RANTES and MIP-1alpha production decreased during HAART at levels closer to that determined with normal controls, while MIP-1beta production was less consistently modified. These data indicate that the expression of chemokine receptors CCR5 and CXCR4 and the production of beta-chemokines are altered in HIV-infected individuals, and suggest that their early modifications during HAART reflect both the peripheral redistribution of naive/memory T cell compartments and the decrease in levels of T cell activation. Such modifications in the expression of host determinants of viral tropism and the production of anti-viral molecules may play a role in the emergence of virus variants when a failure of HAART occurs.
Topics: Adult; Anti-HIV Agents; Antigens, CD; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chemokine CCL3; Chemokine CCL4; Chemokine CCL5; Chemokines, CC; Drug Therapy, Combination; Female; Flow Cytometry; HIV Infections; Humans; Lectins; Macrophage Inflammatory Proteins; Male; Middle Aged; Receptors, CCR5; Receptors, CXCR4; T-Lymphocytes; Time Factors; Viral Load
PubMed: 10540164
DOI: 10.1046/j.1365-2249.1999.01033.x -
Infection and Immunity Jul 2005Chemokines regulate the host immune response to a variety of infectious pathogens. Since the role of chemokines in regulating host immunity in children with Plasmodium...
Chemokines regulate the host immune response to a variety of infectious pathogens. Since the role of chemokines in regulating host immunity in children with Plasmodium falciparum malaria has not previously been reported, circulating levels of beta-chemokines (MIP-1alpha, MIP-1beta, and RANTES) and their respective transcriptional profiles in ex vivo peripheral blood mononuclear cells (PBMCs) were investigated. Peripheral blood MIP-1alpha and MIP-1beta levels were significantly elevated in mild and severe malaria, while RANTES levels decreased with increasing disease severity. Beta-chemokine gene expression profiles in blood mononuclear cells closely matched those of circulating beta-chemokines, illustrating that PBMCs are a primary source for the observed pattern of beta-chemokine production during acute malaria. Statistical modeling revealed that none of the chemokines was significantly associated with either parasitemia or anemia. Additional investigations in healthy children with a known history of malaria showed that children with prior severe malaria had significantly lower baseline RANTES production than children with a history of mild malaria, suggesting inherent differences in the ability to produce RANTES in these two groups. Baseline MIP-1alpha and MIP-1beta did not significantly differ between children with prior severe malaria and those with mild malaria. Additional in vitro experiments in PBMCs from healthy, malaria-naïve donors revealed that P. falciparum-derived hemozoin (Hz; malarial pigment) and synthetic Hz (beta-hematin) promote a similar pattern of beta-chemokine gene expression. Taken together, the results presented here demonstrate that children with severe malaria have a distinct profile of beta-chemokines characterized by increased circulating levels of MIP-1alpha and MIP-1beta and decreased RANTES. Altered patterns of circulating beta-chemokines result, at least in part, from Hz-induced changes in beta-chemokine gene expression in blood mononuclear cells.
Topics: Chemokine CCL3; Chemokine CCL4; Chemokine CCL5; Child; Child, Preschool; Female; Gene Expression Profiling; Hemeproteins; Hemoglobins; Humans; Macrophage Inflammatory Proteins; Malaria, Falciparum; Male
PubMed: 15972509
DOI: 10.1128/IAI.73.7.4190-4197.2005 -
Arthritis and Rheumatism Aug 2000Human chondrocytes produce different C-X-C and C-C chemokines under basal conditions and upon activation with proinflammatory cytokines. We investigated whether human...
OBJECTIVE
Human chondrocytes produce different C-X-C and C-C chemokines under basal conditions and upon activation with proinflammatory cytokines. We investigated whether human chondrocytes also have chemokine receptors and examined the effects of chemokines on chondrocyte activity.
METHODS
The expression of chemokine receptors was determined by immunochemical analysis of frozen sections from normal and osteoarthritic cartilage and by flow cytometry of isolated cells. The messenger RNA expression for chemokine receptors was studied by reverse transcriptase-polymerase chain reaction. Isolated chondrocytes were stimulated with different chemokines, and the responses were evaluated by assaying the release of matrix metalloprotease 3 (MMP-3) and of the lysosomal enzyme N-acetyl-beta-D-glucosaminidase in the supernatants.
RESULTS
A wide variety of chemokine receptors (CCR-1, CCR-2, CCR-3, CCR-5, CXCR-1, and CXCR-2) was detected on human chondrocytes. Interaction of these receptors with the corresponding ligands induced the release of MMP-3. This response was abrogated by pretreatment of the cells with Bordetella pertussis toxin, demonstrating involvement of G proteins of the Gi type. The response decreased in the presence of cycloheximide, indicating dependence on protein synthesis. Chemokines also induced the exocytosis of N-acetyl-beta-D-glucosaminidase, which was prevented by receptor blockage with anti-CCR-3 and by treatment with B pertussis toxin. Chondrocytes obtained from osteoarthritic tissue showed an increased expression of CCR-3 and possibly of CXCR-1, and an augmented release of matrix-degrading enzymes compared with chondrocytes from normal donors.
CONCLUSION
Our findings suggest the existence in human chondrocytes of a novel catabolic pathway, primed by chemokines and their receptors, that leads to the breakdown of cartilage matrix components.
Topics: Acetylglucosaminidase; Chemokines, CC; Chemokines, CXC; Chondrocytes; Exocytosis; Humans; Matrix Metalloproteinase 3; Receptors, Chemokine
PubMed: 10943863
DOI: 10.1002/1529-0131(200008)43:8<1734::AID-ANR9>3.0.CO;2-B -
The Journal of Biological Chemistry Mar 2013Chemokine receptors form a large subfamily of G protein-coupled receptors that predominantly activate heterotrimeric Gi proteins and are involved in immune cell...
Chemokine receptors form a large subfamily of G protein-coupled receptors that predominantly activate heterotrimeric Gi proteins and are involved in immune cell migration. CCX-CKR is an atypical chemokine receptor with high affinity for CCL19, CCL21, and CCL25 chemokines, but is not known to activate intracellular signaling pathways. However, CCX-CKR acts as decoy receptor and efficiently internalizes these chemokines, thereby preventing their interaction with other chemokine receptors, like CCR7 and CCR9. Internalization of fluorescently labeled CCL19 correlated with β-arrestin2-GFP translocation. Moreover, recruitment of β-arrestins to CCX-CKR in response to CCL19, CCL21, and CCL25 was demonstrated using enzyme-fragment complementation and bioluminescence resonance energy transfer methods. To unravel why CCX-CKR is unable to activate Gi signaling, CCX-CKR chimeras were constructed by substituting its intracellular loops with the corresponding CCR7 or CCR9 domains. The signaling properties of chimeric CCX-CKR receptors were characterized using a cAMP-responsive element (CRE)-driven reporter gene assay. Unexpectedly, wild type CCX-CKR and a subset of the chimeras induced an increase in CRE activity in response to CCL19, CCL21, and CCL25 in the presence of the Gi inhibitor pertussis toxin. CCX-CKR signaling to CRE required an intact DRY motif. These data suggest that inactive Gi proteins impair CCX-CKR signaling most likely by hindering the interaction of this receptor with pertussis toxin-insensitive G proteins that transduce signaling to CRE. On the other hand, recruitment of the putative signaling scaffold β-arrestin to CCX-CKR in response to chemokines might allow activation of yet to be identified signal transduction pathways.
Topics: Animals; Arrestins; Binding, Competitive; Blotting, Western; CHO Cells; Cell Line, Tumor; Chemokine CCL19; Chemokine CCL21; Chemokines, CC; Cricetinae; Cricetulus; GTP-Binding Protein alpha Subunits, Gi-Go; Green Fluorescent Proteins; HEK293 Cells; Humans; Microscopy, Fluorescence; Models, Biological; Pertussis Toxin; Protein Binding; Protein Transport; Receptors, CCR; Signal Transduction; beta-Arrestins
PubMed: 23341447
DOI: 10.1074/jbc.M112.406108