Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: HUMANGGP:023668 (CCL4)
 1,152 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immune system attempts to prevent or limit tumor growth, yet efforts to induce responses to tumors yield minimal results, rendering tumors virtually invisible to the immune system [1]. Several mechanisms may account for this subversion, including the triggering of tolerance to tumor antigens [2, 3], TGF-alpha or IL-10 production, downregulation of MHC molecules, or upregulation of FasL expression [4, 5]. Melanoma cells may in some instances use FasL expression to protect themselves against tumor-infiltrating lymphocytes (TIL) [4, 5]. Here, we show another, chemokine-dependent mechanism by which melanoma tumor cells shield themselves from immune reactions. Melanoma-inducible CCL5 (RANTES) production by infiltrating CD8 cells activates an apoptotic pathway in TIL involving cytochrome c release into the cytosol and activation of caspase-9 and -3. This process, triggered by CCL5 binding to CCR5, is not mediated by TNFalpha, Fas, or caspase-8. The effect is not unique to CCL5, as other CCR5 ligands such as CCL3 (MIP-1alpha) and CCL4 (MIP-1beta) also trigger TIL cell death, nor is it limited to melanoma cells, as it also operates in activated primary T lymphocytes. The model assigns a role to the CXC chemokine CXCL12 (SDF-1alpha) in this process, as this melanoma cell-produced chemokine upregulates CCL5 production by TIL, initiating TIL cell death.
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PMID:A potential immune escape mechanism by melanoma cells through the activation of chemokine-induced T cell death. 1136 32

Development of allergic contact dermatitis to haptens depends upon a balance between CD8(+) T lymphocytes with pathogenic activity and CD4(+) T cells, which comprise both effector and regulatory cells. Thus, differential recruitment of CD8(+) and CD4(+) lymphocytes to sites of hapten challenge may have considerable impact on disease expression. Here the migration of cutaneous lymphocyte-associated antigen+, nickel-specific CD8(+) and CD4(+) T cell lines were compared with a panel of chemokines produced in the skin during allergic contact dermatitis. CCL17/TARC and CCL22/MDC induced a 3-fold higher migration of CD4(+) compared with CD8(+) lymphocytes. In contrast, CXCL10/IP-10 was 2-fold more potent in attracting CD8(+) cells. These findings were consistent with the higher expression of CCR4 and CXCR3 on CD4(+) and CD8(+) T cell lines, respectively. Moreover, CCR4 expression was high on nickel-specific T helper 2, intermediate on T helper 1 and T cytotoxic 2, and almost undetectable on T cytotoxic 1 clones. On the contrary, CXCR3 was expressed by T cytotoxic 1 and 2 and T helper 1, but not T helper 2 clones. Reverse transcription-polymerase chain reaction analysis of the skin before and after hapten challenge revealed the constitutive presence of TARC, and the early appearance of CCL2/MCP-1, followed by IP-10, CCL4/MIP-1beta, and MDC mRNA. Supernatants from activated keratinocytes induced a strong migration of CD8(+) lymphocytes, which was blocked by neutralization of IP-10. Conversely, supernatants from immature and mature dendritic cells attracted mostly CD4(+) lymphocytes in a TARC- and MDC-dependent manner. Our data indicate that distinct chemokines and cell types control the accumulation of CD8(+) and CD4(+) T cells within inflamed skin.
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PMID:Nickel-specific CD4(+) and CD8(+) T cells display distinct migratory responses to chemokines produced during allergic contact dermatitis. 1206 Apr 2

Interleukin (IL)-12, especially in the presence of neutralizing anti-IL-4 monoclonal antibodies, primed CD45RO(-) T clones for high CCL3/macrophage-inflammatory protein-1alpha (MIP-1alpha) and CCL4/MIP-1beta levels. In CD4(+) and CD8(+) clones from two patients deficient for IL-12Rbeta1 (IL-12Rbeta1(-/-)), production of CCL3/MIP-1alpha and CCL4/MIP-1beta was defective. CD4(+) clones from two patients deficient for interferon-gamma (IFN-gamma) R1 (IFN-gammaR1(-/-)) produced somewhat decreased CCL4/MIP-1beta levels. IL-12 failed to prime CD4(+) or CD8(+) healthy clones for high CCL5/regulated on activation, normal T expressed and secreted (RANTES) production, although its secretion was impaired in CD4(+) clones from IL-12Rbeta1(-/-) and IFN-gammaR1(-/-) patients. CCR5 surface expression was up-regulated in resting peripheral blood mononuclear cells and CD4(+) clones from both kinds of patients, rendering them more susceptible to CCR5-dependent (R5) HIV-1 infection. Neutralization of IFN-gamma increased CCR5 expression and decreased CC-chemokine secretion by CD4(+) clones from healthy and IL-12Rbeta1(-/-) individuals, suggesting an IFN-gamma-dependent control of CCR5 expression. These data provide the first documented analysis of chemokine secretion and chemokine receptor expression on T cells from IL-12 and IFN-gamma receptor-deficient patients and dissect the role of IL-12 and IFN-gamma on inducing inflammatory chemokine secretion and down-regulating CCR5 expression in human T cells.
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PMID:IFN-gamma and IL-12 differentially regulate CC-chemokine secretion and CCR5 expression in human T lymphocytes. 1237 43

We recently reported that dendritic cells (DC) infected with Mycobacterium tuberculosis (Mtb) produce Th1/IFN-gamma-inducing cytokines, IFN-alpha beta and IL-12. In the present article, we show that maturing Mtb-infected DC express high levels of CCR7 and they become responsive to its ligand CCL21. Conversely, CCR5 expression was rapidly lost from the cell surface following Mtb infection. High levels of CCL3 and CCL4 were produced within 8 h after infection, which is likely to account for the observed CCR5 down-modulation on Mtb-infected DC. In addition, Mtb infection stimulated the secretion of CXCL9 and CXCL10. Interestingly, the synthesis of CXCL10 was mainly dependent on the Mtb-induced production of IFN-alpha beta. Indeed, IFN-alpha beta neutralization down-regulated CXCL10 expression, whereas the expression of CXCL9 appeared to be unaffected. The chemotactic activity of the Mtb-infected DC supernatants was evaluated by migration assays using activated NK, CD4(+), and CD8(+) cells that expressed both CCR5 and CXCR3. Mtb-induced expression of CCL3, CCL4, CXCL9, and CXCL10 was involved in the stimulation of NK and T cell migration. In accordance with the data on the IFN-alpha beta-induced expression of CXCL10, neutralization of IFN-alpha beta significantly reduced the chemotactic activity of the supernatant from Mtb-infected DC. This indicates that IFN-alpha beta may modulate the immune response through the expression of CXCL10, which along with CXCL9, CCL3, and CCL4 participates in the recruitment and selective homing of activated/effector cells, which are known to accumulate at the site of Mtb infection and take part in the formation of the granulomas.
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PMID:IFN-alpha beta released by Mycobacterium tuberculosis-infected human dendritic cells induces the expression of CXCL10: selective recruitment of NK and activated T cells. 1253 73

Human CCL4/macrophage inflammatory protein (MIP)-1beta and CCL3/MIP-1alpha are two highly related molecules that belong to a cluster of inflammatory CC chemokines located in chromosome 17. CCL4 and CCL3 were formed by duplication of a common ancestral gene, generating the SCYA4 and SCYA3 genes which, in turn, present a variable number of additional non-allelic copies (SCYA4L and SCYA3L1). In this study, we show that both CCL4 loci (SCYA4 and SCYA4L) are expressed and alternatively generate spliced variants lacking the second exon. In addition, we found that the SCYA4L locus is polymorphic and displays a second allelic variant (hereinafter SCYA4L2) with a nucleotide change in the intron 2 acceptor splice site compared with the one described originally (hereinafter SCYA4L1). Therefore, the pattern of SCYA4L2 transcripts is completely different from that of SCYA4L1, since SCYA4L2 uses several new acceptor splice sites and generates nine new mRNAs. Furthermore, we analyzed the contribution of each locus (SCYA4 and SCYA4L1/L2) to total CCL4 expression in human CD8 T cells by RT-amplified fragment length polymorphism and real-time PCR, and we found that L2 homozygous individuals (L2L2) only express half the levels of CCL4 compared with L1L1 individuals. The analysis of transcripts from the SCYA4L locus showed a lower level in L2 homozygous compared with L1 homozygous individuals (12% vs 52% of total CCL4 transcripts). A possible clinical relevance of these CCL4 allelic variants was suggested by the higher frequency of the L2 allele in a group of HIV(+) individuals (n = 175) when compared with controls (n = 220, 28.6% vs 16.6% (p = 0.00016)).
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PMID:Multiple products derived from two CCL4 loci: high incidence of a new polymorphism in HIV+ patients. 1584 66

Although the pathogenesis of periodontal disease (PD) is not well known, cytokines, chemotactic factors and inflammatory cells are certainly involved in the disease outcome. Here, we characterized the evolution of the PD induced by Actinobacillus actinomycetemcomitans in mice, showing that oral inoculation of these bacteria leads to the migration of leukocytes to periodontal tissues and marked alveolar bone resorption. We found the expression of pro-inflammatory and Th1-type cytokines including TNF-alpha, IFN-gamma and IL-12 in periodontal tissues after infection with A. actinomycetemcomitans, from the early stages after infection and throughout the course of the disease. Similar kinetics of expression were found for the chemokines CCL5, CCL4, CCL3 and CXCL10 and for the receptors CCR5 and CXCR3, all of them linked to the Th1-type pattern. The expression of the Th2-type mediators IL-10, CCL1 and their receptors CCR4 and CCR8 was detected only after 30 days of infection, determining a time-dependent mixed pattern of polarized immune response. The chemokine expression was correlated with the presence of polymorphonuclear leukocytes, macrophages, CD4 and CD8 lymphocytes, and B cells in the inflammatory infiltrate. Interestingly, during the predominance of the Th1-type response, a sharp increase in the number of inflammatory cells and intense bone loss was seen. By contrast, after the increased expression of Th2-type mediators, the number of inflammatory cells remained constant. Our data demonstrate that mice subjected to oral inoculation of A. actinomycetemcomitans represent a useful model for the study of PD. In addition, our results suggest that expression of cytokines and chemokines can drive the selective recruitment of leukocyte subsets to periodontal tissues, which could determine the stable or progressive nature of the lesion.
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PMID:Actinobacillus actinomycetemcomitans-induced periodontal disease in mice: patterns of cytokine, chemokine, and chemokine receptor expression and leukocyte migration. 1585 Jul 60

The hypothesis was tested that mucosal stimulation with unmatched mononuclear cells would induce systemic alloimmune responses. Rectal or vaginal mucosal administration of 10(4)-10(7) unmatched mononuclear cells induced significant dose-dependent T-cell proliferation stimulated by the allogeneic cells in rhesus macaques. This was associated with a significant upregulation of CD8(+) T-cell-derived suppressor factor, as well as the CC chemokines CCL3, CCL4 and CCL5. In addition, there was a dose-dependent increase in antibodies to CCR5. These responses were associated with decreased in vitro simian immunodeficiency virus (SIV) infectivity of CD4(+) T cells. A further investigation of SIV infectivity of CD4(+) T cells separated from multiparous macaques also showed significant inhibition compared with male macaques. It is suggested that vaginal or rectal exposure to allogeneic stimulation by a partner's HLA antigens in seminal fluid, as occurs during sexual intercourse, or immunization by semi-allogeneic fetuses in multiparous females may elicit protection against SIV or human immunodeficiency virus infection.
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PMID:Mucosal alloimmunization elicits T-cell proliferation, CC chemokines, CCR5 antibodies and inhibition of simian immunodeficiency virus infectivity. 1603 70

The clinical picture of severe acute respiratory syndrome (SARS) is characterized by pulmonary inflammation and respiratory failure, resembling that of acute respiratory distress syndrome. However, the events that lead to the recruitment of leukocytes are poorly understood. To study the cellular response in the acute phase of SARS coronavirus (SARS-CoV)-host cell interaction, we investigated the induction of chemokines, adhesion molecules, and DC-SIGN (dendritic cell-specific ICAM-3-grabbing nonintegrin) by SARS-CoV. Immunohistochemistry revealed neutrophil, macrophage, and CD8 T-cell infiltration in the lung autopsy of a SARS patient who died during the acute phase of illness. Additionally, pneumocytes and macrophages in the patient's lung expressed P-selectin and DC-SIGN. In in vitro study, we showed that the A549 and THP-1 cell lines were susceptible to SARS-CoV. A549 cells produced CCL2/monocyte chemoattractant protein 1 (MCP-1) and CXCL8/interleukin-8 (IL-8) after interaction with SARS-CoV and expressed P-selectin and VCAM-1. Moreover, SARS-CoV induced THP-1 cells to express CCL2/MCP-1, CXCL8/IL-8, CCL3/MIP-1alpha, CXCL10/IP-10, CCL4/MIP-1beta, and CCL5/RANTES, which attracted neutrophils, monocytes, and activated T cells in a chemotaxis assay. We also demonstrated that DC-SIGN was inducible in THP-1 as well as A549 cells after SARS-CoV infection. Our in vitro experiments modeling infection in humans together with the study of a lung biopsy of a patient who died during the early phase of infection demonstrated that SARS-CoV, through a dynamic interaction with lung epithelial cells and monocytic cells, creates an environment conducive for immune cell migration and accumulation that eventually leads to lung injury.
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PMID:Modeling the early events of severe acute respiratory syndrome coronavirus infection in vitro. 1650 Oct 78

Periplocoside E (PSE) was found to inhibit primary T-cell activation in our previous study. Now we examined the effect and mechanisms of PSE on the central nervous system (CNS) demyelination in experimental allergic encephalomyelitis (EAE). C57BL/6 mice immunized with myelin oligodendrocyte glyco-protein (MOG) were treated with PSE following immunization and continued throughout the study. The effect on the progression of EAE and other relevant parameters were assessed. PSE reduced the incidence and severity of EAE. Spinal cord histopathology analysis showed that the therapeutic effect of PSE was associated with reduced mononuclear cell infiltration and CNS inflammation. As reverse transcription-polymerase chain reaction analysis showed, PSE decreased the CD4(+), CD8(+), and CD11b(+) cell infiltration. T cells from lymph nodes of MOG-immunized mice expressed enhanced levels of CCR5 and CXCR3 mRNA compared with T cells from normal mice. However, CCR5 and CXCR3 expressions were suppressed in T cells from PSE-treated mice. In vitro study also showed PSE inhibited interferon (IFN)-gamma-dependent CXCR3 expression in T cells through suppressing T-cell receptor (TCR) ligation-induced IFN-gamma production, whereas it inhibited interleukin (IL)-12-dependent CCR5 expression through suppressing IL-12 reactivity in TCR-triggered T cells. As a result, the initial influx of T cells into CNS was inhibited in PSE-treated mice. The consequent activation of macrophages/microglia cells was inhibited in spinal cord from PSE-treated mice as determination of chemokine expressions (CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10). Consistently, the secondary influx of CD4(+), CD8(+), and CD11b(+) cells was decreased in spinal cords from PSE-treated mice. These findings suggest the potential therapeutic effect of PSE on multiple sclerosis.
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PMID:Periplocoside E inhibits experimental allergic encephalomyelitis by suppressing interleukin 12-dependent CCR5 expression and interferon-gamma-dependent CXCR3 expression in T lymphocytes. 1675 Dec 52

CCL3 (MIP-1 alpha), CCL4 (MIP-1 beta), and CCL18 (DC-CK1/PARC/AMAC-1) are potent chemoattractants produced by macrophages, natural killer cells, fibroblasts, mast cells, CD4(+) T cells, and CD8(+) T cells. CCL3 and CCL4 are natural ligands for the primary human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 and are also known to activate and enhance the cytotoxicity of natural killer cells. Genomic DNAs from >3,000 participants enrolled in five United States-based natural-history cohorts with acquired immunodeficiency syndrome (AIDS) were genotyped for 21 single-nucleotide polymorphisms (SNPs) in a 47-kb interval on chromosome 17q12 containing the genes CCL3, CCL4, and CCL18. All 21 SNPs were polymorphic in African Americans (AAs), whereas 7 of the 21 had minor-allele frequencies <0.01 in European Americans (EAs). Substantial linkage disequilibrium was observed in a 37-kb interval containing 17 SNPs where many pairwise D' values exceeded 0.70 in both racial groups, but particularly in EAs. Four and three haplotype blocks were observed in AAs and EAs, respectively. Blocks were strongly correlated with each other, and common haplotype diversity within blocks was limited. Two significant associations are reported that replicate an earlier study. First, among AA members of the AIDS Link to the Intravenous Experience cohort of injection drug users, frequencies of three correlated SNPs covering 2,231 bp in CCL3 were significantly elevated among highly exposed, persistently HIV-1-uninfected individuals compared with HIV-1-infected seroconvertors (P = .02-.03). Second, seven highly correlated SNPs spanning 36 kb and containing all three genes were significantly associated with more-rapid disease progression among EAs enrolled in the Multicenter AIDS Cohort Study cohort (P = .01-.02). These results reiterate the importance of chemokine gene variation in HIV-1/AIDS pathogenesis and emphasize that localized linkage disequilibrium makes the identification of causal mutations difficult.
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PMID:Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV Type 1 transmission and AIDS disease progression. 1677 71


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