Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemokines are secreted proteins that function as chemoattractants, mediating the recruitment of specific subsets of leukocytes to sites of tissue damage and immunological reactions. Chemokines may also function as antiviral agents, since viruses such as human immunodeficiency virus type 1 (HIV-1) use chemokine receptors as co-receptors for viral entry. This study examines whether virus-induced interferon, IFNbeta, or immune-related interferon, IFNgamma, affects the production of beta-chemokines by CNS microglia and peripheral monocytes. When IFNbeta was used as the stimulus, induction of MIP-1alpha, MIP-1beta, MCP-1, and RANTES mRNA and protein was observed within 12 h of stimulation in microglia. By contrast, when IFNgamma was used as the stimulus, only MCP-1 was induced. IFNbeta stimulation of blood monocytes resulted in upregulation of MIP-1alpha, MIP-1beta, and MCP-1. Thus, type I and II interferons differentially regulate beta-chemokines in human fetal microglia and peripheral blood monocytes. These observations may have relevance for the therapeutic activity of IFNbeta in multiple sclerosis and for the antiviral effects of IFNbeta for HIV-1 infection of monocytes and microglia.
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PMID:Differential induction of chemokines in human microglia by type I and II interferons. 1064 53

Chemokines are pro-inflammatory cytokines that inhibit human immunodeficiency virus type 1 (HIV-1) replication in vitro. We studied the kinetics of the beta-chemokines, macrophage inhibitory protein (MIP)-1 alpha, MIP-1 beta, RANTES, and monocyte chemotactic protein (MCP)-1 in plasma during 12 months of antiretroviral therapy in 26 HIV-1-infected patients and in 11 untreated subjects. Eleven patients with moderate immunodeficiency had HIV-1 RNA levels < 50 copies/ml after 1 year, whereas 12 out of 15 patients with severe immunodeficiency had detectable virus. At baseline, MCP-1 levels correlated positively with HIV-1 RNA and DNA levels and inversely with CD4 cell counts. A reverse pattern was seen for the MIP-1 beta levels. No correlation was seen between MIP-1 alpha or RANTES and any of the parameters. Also, there was a dichotomy between the different beta-chemokines in response to therapy. Decreases of MCP-1 and RANTES levels were found, but no durable changes of MIP-1 alpha and MIP-1 beta. The MCP-1 levels rebounded back to baseline after 1 year in the patients who responded virologically, which could possibly reflect an increased immune activation. The biological consequences of the changes in beta-chemokines levels during antiretroviral treatment are still unknown and deserve further studies.
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PMID:Kinetics of beta-chemokine levels during anti-HIV therapy. 1068 56

Interleukin 7 (IL-7) protein has been reported to be important in the development of cytotoxic-T-lymphocyte (CTL) responses. However, other studies also support a partial Th2 phenotype for this cytokine. In an effort to clarify this unusual conflict, we compared IL-7 along with IL-12 (Th1 control) and IL-10 (Th2 control) for its ability to induce antigen (Ag)-specific CTL and Th1- versus Th2-type immune responses using a well established DNA vaccine model. In particular, IL-7 codelivery showed a significant increase in immunoglobulin G1 (IgG1) levels compared to IgG2a levels. IL-7 coinjection also decreased production of Th1-type cytokine IL-2, gamma interferon, and the chemokine RANTES but increased production of the Th2-type cytokine IL-10 and the similarly biased chemokine MCP-1. In herpes simplex virus (HSV) challenge studies, IL-7 coinjection decreased the survival rate after lethal HSV type 2 (HSV-2) challenge compared with gD plasmid vaccine alone in a manner similar to IL-10 coinjection, whereas IL-12 coinjection enhanced the protection, further supporting that IL-7 drives immune responses to the Th2 type, resulting in reduced protection against HSV-2 challenge. Moreover, coinjection with human immunodeficiency virus type 1 env and gag/pol genes plus IL-12 or IL-7 cDNA enhanced Ag-specific CTLs, while coinjection with IL-10 cDNA failed to influence CTL induction. Thus, IL-7 could drive Ag-specific Th2-type cellular responses and/or CTL responses. These results support that CTLs could be induced by IL-7 in a Th2-type cytokine and chemokine environment in vivo. This property of IL-7 allows for an alternative pathway for CTL development which has important implications for host-pathogen responses.
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PMID:Interleukin 7 can enhance antigen-specific cytotoxic-T-lymphocyte and/or Th2-type immune responses in vivo. 1097 49

A finding commonly observed in human immunodeficiency virus type 1 (HIV-1)-infected patients is invasion of the brain by activated T cells and infected macrophages, eventually leading to the development of neurological disorders and HIV-1-associated dementia. The recruitment of T cells and macrophages into the brain is likely the result of chemokine expression. Indeed, earlier studies revealed that levels of different chemokines were increased in the cerebrospinal fluid of HIV-1-infected patients whereas possible triggers and cellular sources for chemokine expression in the brain remain widely undefined. As previous studies indicated that HIV-1 Tat, the retroviral transactivator, is capable of inducing a variety of cellular genes, we investigated its capacity to induce production of chemokines in astrocytes. Herein, we demonstrate that HIV-1 Tat(72aa) is a potent inducer of MCP-1, interleukin-8 (IL-8), and IP-10 expression in astrocytes. Levels of induced IP-10 protein were sufficiently high to induce chemotaxis of peripheral blood lymphocytes. In addition, Tat(72aa) induced IL-8 expression in astrocytes. IL-8 mRNA induction was seen less then 1 h after Tat(72aa) stimulation, and levels remained elevated for up to 24 h, leading to IL-8 protein production. Tat(72aa)-mediated MCP-1 and IL-8 mRNA induction was susceptible to inhibition by the MEK1/2 inhibitor UO126 but was only modestly decreased by the inclusion of the p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190. In contrast, Tat-mediated IP-10 mRNA induction was suppressed by SB202190 but not by the MEK1/2 inhibitor UO126. These findings indicate that MAPKs play a major role in Tat(72aa)-mediated chemokine induction in astrocytes.
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PMID:Induction of the chemokines interleukin-8 and IP-10 by human immunodeficiency virus type 1 tat in astrocytes. 1098 68

The CXC chemokine gamma interferon (IFN-gamma)-inducible protein CXCL10/IP-10 is markedly elevated in cerebrospinal fluid and brain of individuals infected with human immunodeficiency virus type 1 (HIV-1) and is implicated in the pathogenesis of HIV-associated dementia (HAD). To explore the possible role of CXCL10/IP-10 in HAD, we examined the expression of this and other chemokines in the central nervous system (CNS) of transgenic mice with astrocyte-targeted expression of HIV gp120 under the control of the glial fibrillary acidic protein (GFAP) promoter, a murine model for HIV-1 encephalopathy. Compared with wild-type controls, CNS expression of the CC chemokine gene CCL2/MCP-1 and the CXC chemokine genes CXCL10/IP-10 and CXCL9/Mig was induced in the GFAP-HIV gp120 mice. CXCL10/IP-10 RNA expression was increased most and overlapped the expression of the transgene-encoded HIV gp120 gene. Astrocytes and to a lesser extent microglia were identified as the major cellular sites for CXCL10/IP-10 gene expression. There was no detectable expression of any class of IFN or their responsive genes. In astrocyte cultures, soluble recombinant HIV gp120 protein was capable of directly inducing CXCL10/IP-10 gene expression a process that was independent of STAT1. These findings highlight a novel IFN- and STAT1-independent mechanism for the regulation of CXCL10/IP-10 expression and directly link expression of HIV gp120 to the induction of CXCL10/IP-10 that is found in HIV infection of the CNS. Finally, one function of IP-10 expression may be the recruitment of leukocytes to the CNS, since the brain of GFAP-HIV gp120 mice had increased numbers of CD3(+) T cells that were found in close proximity to sites of CXCL10/IP-10 RNA expression.
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PMID:Interferon-independent, human immunodeficiency virus type 1 gp120-mediated induction of CXCL10/IP-10 gene expression by astrocytes in vivo and in vitro. 1143 87

CD40 is a protein on microglia that is up-regulated with interferon (IFN)-gamma and is engaged by CD40L, found on CD4+ T cells, B cells, and monocytes. These interactions may be important in central nervous system inflammatory diseases. Microglia have been shown to be a source of chemokines, whose expression plays a key role in central nervous system pathologies. We examined the expression of CD40 on microglia in human immunodeficiency virus (HIV) encephalitic brain, and the effects of CD40-CD40L interactions on the expression of chemokines by cultured microglia. We found significantly increased numbers of CD40-positive microglia in HIV-infected brain tissue. Treatment of cultured microglia with IFN-gamma and CD40L increased expression of several chemokines. IFN-gamma- and CD40L-induced MCP-1 protein was mediated by activation of the ERK1/2 MAPK pathway, and Western blot analysis demonstrated phosphorylation of ERK1/2 upon stimulation of microglia. In contrast, IFN-gamma- and CD40L-induced IP-10 protein production was mediated by the p38 MAPK pathway. Our data suggest a mechanism whereby CD40L+ cells can induce microglia to secrete chemokines, amplifying inflammatory processes seen in HIV encephalitis and multiple sclerosis, and implicate CD40-CD40L interactions as a target for interventional strategies.
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PMID:CD40-CD40L interactions induce chemokine expression by human microglia: implications for human immunodeficiency virus encephalitis and multiple sclerosis. 1183 76

Kappa-opioid receptor (KOR) ligands have been reported to alter many cell functions and to exert an immunomodulatory role in the CNS. Astrocytes, the predominant brain cell type, have been implicated in the neuropathogenesis of human immunodeficiency virus type 1 (HIV-1). HIV-1 nuclear protein Tat has been reported to induce production of the chemokine monocyte chemoattractant protein-1 (MCP-1 or CCL2) and to activate nuclear factor kappaB (NF-kappaB) in human astrocytes. In the present study, we investigated whether the synthetic KOR ligand trans-3,4-dichloro-N-methyl-N[2-(1-pyrolidinyl)cyclohexyl]benzeneacetamide methanesulfonate (U50,488) would down-regulate MCP-1 production in primary human astrocytes stimulated by Tat. Treatment of astrocytes with U50,488 inhibited Tat-induced MCP-1 production in a concentration-dependent manner. The KOR-selective antagonist nor-binaltrophimine (nor-BNI) completely blocked the inhibitory effect of U50,488, indicating involvement of KOR. While U50,488 alone had a partial inhibitory effect on constituent NF-kappaB activation, it potently suppressed Tat-induced NF-kappaB activation. These findings suggest that KOR ligands could have an anti-inflammatory effect in the CNS and thereby be beneficial in the treatment of HIV-1-associated brain disease.
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PMID:U50,488 inhibits HIV-1 Tat-induced monocyte chemoattractant protein-1 (CCL2) production by human astrocytes. 1247 73

Acquired immunodeficiency syndrome (AIDS)-associated dementia is often characterized by chronic inflammation, with infected macrophage infiltration of the CNS resulting in the production of human immunodeficiency virus type 1 (HIV-1) products, including tat, and neurotoxins that contribute to neuronal loss. In addition to their established role in leukocyte recruitment and activation, we identified an additional role for chemokines in the CNS. Monocyte chemoattractant protein-1 (MCP-1 or CCL2) and regulated upon activation normal T cell expressed and secreted (RANTES) were found to protect mixed cultures of human neurons and astrocytes from tat or NMDA-induced apoptosis. Neuronal and astrocytic apoptosis in these cultures was significantly inhibited by co-treatment with MCP-1 or RANTES but not IP-10. The protective effect of RANTES was blocked by antibodies to MCP-1, indicating that RANTES protection is mediated by the induction of MCP-1. The NMDA blocker, MK801, also abolished the toxic effects of both tat and NMDA. Tat or NMDA treatment of mixed cultures for 24 h resulted in increased extracellular glutamate ([Glu]e) and NMDA receptor 1 (NMDAR1) expression, potential contributors to apoptosis. Co-treatment with MCP-1 inhibited tat and NMDA-induced increases in [Glu]e and NMDAR1, and also reduced the levels and number of neurons containing intracellular tat. These data indicate that MCP-1 may play a novel role as a protective agent against the toxic effects of glutamate and tat.
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PMID:MCP-1 (CCL2) protects human neurons and astrocytes from NMDA or HIV-tat-induced apoptosis. 1275 88

CCR5 is a G protein-coupled receptor for RANTES, MIP-1alpha, MIP-1beta, and MCP-2 that functions as the front line coreceptor for human immunodeficiency virus type 1 infection. To elucidate the mechanism for CCR5 activation, this coreceptor was expressed in yeast coupled to the pheromone response pathway and a constitutively active mutant (CAM) was derived by random mutagenesis. Conversion of Thr-82 in the highly conserved TXP motif in transmembrane helix 2 to Pro, His, Tyr, Arg, or Lys conferred autonomous signaling activity in yeast and mammalian cells. This substitution also imparted constitutive signaling to CCR2 in yeast and mammalian cells, but not CCR1, CCR3, CCR4, CXCR2, or CXCR4. The CCR5-CAM, but not the CCR2-CAM had a reduction in ligand binding affinity. Whereas the amplitude of calcium mobilization induced by RANTES stimulation was lower in the CCR5-CAM than the wild-type (WT) receptor, MCP-1 induced a higher signal in the CCR2-CAM than in CCR2-WT. The chemotactic response of CCR5-CAM(T82P) to RANTES was similar to that of CCR5-WT, but CCR5-CAM(T82K) was dramatically decreased. The chemotactic response of CCR2-WT and CCR2-CAM(T94K) were similar. These findings extend insight into the role of the TXP motif in the mechanism for CCR5 signaling. CCR2, the receptor most closely genetically related to CCR5, shared a similar signaling mechanism, but other receptors containing the TXP motif did not. The expression of CCR5 and CCR2 in yeast and the availability of variants with autonomous signaling represent critical tools for characterizing receptor antagonists and developing approaches to block their role in human diseases.
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PMID:Constitutive activation of CCR5 and CCR2 induced by conformational changes in the conserved TXP motif in transmembrane helix 2. 1283 56

The potential of a dendritic cell (DC)-based vaccine against human immunodeficiency virus type 1 (HIV-1) infection in humans was explored with SCID mice reconstituted with human peripheral blood mononuclear cells (PBMC). HIV-1-negative normal human PBMC were transplanted directly into the spleens of SCID mice (hu-PBL-SCID-spl mice) together with autologous mature DCs pulsed with either inactivated HIV-1 (strain R5 or X4) or ovalbumin (OVA), followed by a booster injection 5 days later with autologous DCs pulsed with the same respective antigens. Five days later, these mice were challenged intraperitoneally with R5 HIV-1(JR-CSF). Analysis of infection at 7 days postinfection showed that the DC-HIV-1-immunized hu-PBL-SCID-spl mice, irrespective of the HIV-1 isolate used for immunization, were protected against HIV-1 infection. In contrast, none of the DC-OVA-immunized mice were protected. Sera from the DC-HIV-1- but not the DC-OVA-immunized mice inhibited the in vitro infection of activated PBMC and macrophages with R5, but not X4, HIV-1. Upon restimulation with HIV-1 in vitro, the human CD4(+) T cells derived from the DC-HIV-1-immunized mice produced a similar R5 HIV-1 suppressor factor. Neutralizing antibodies against human RANTES, MIP-1alpha, MIP-1beta, alpha interferon (IFN-alpha), IFN-beta, IFN-gamma, interleukin-4 (IL-4), IL-10, IL-13, IL-16, MCP-1, MCP-3, tumor necrosis factor alpha (TNF-alpha), or TNF-beta failed to reverse the HIV-1-suppressive activity. These results show that inactivated HIV-1-pulsed autologous DCs can stimulate splenic resident human CD4(+) T cells in hu-PBL-SCID-spl mice to produce a yet-to-be-defined, novel soluble factor(s) with protective properties against R5 HIV-1 infection.
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PMID:Induction of protective immune responses against R5 human immunodeficiency virus type 1 (HIV-1) infection in hu-PBL-SCID mice by intrasplenic immunization with HIV-1-pulsed dendritic cells: possible involvement of a novel factor of human CD4(+) T-cell origin. 1288 91


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