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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 -
PLoS Pathogens Oct 2009Induction of a functional subset of HIV-specific CD4+ T cells that is resistant to HIV infection could enhance immune protection and decrease the rate of HIV disease...
Induction of a functional subset of HIV-specific CD4+ T cells that is resistant to HIV infection could enhance immune protection and decrease the rate of HIV disease progression. CMV-specific CD4+ T cells, which are less frequently infected than HIV-specific CD4+ T cells, are a model for such an effect. To determine the mechanism of this protection, we compared the functional response of HIV gag-specific and CMV pp65-specific CD4+ T cells in individuals co-infected with CMV and HIV. We found that CMV-specific CD4+ T cells rapidly up-regulated production of MIP-1alpha and MIP-1beta mRNA, resulting in a rapid increase in production of MIP-1alpha and MIP-1beta after cognate antigen stimulation. Production of beta-chemokines was associated with maturational phenotype and was rarely seen in HIV-specific CD4+ T cells. To test whether production of beta-chemokines by CD4+ T cells lowers their susceptibility to HIV infection, we measured cell-associated Gag DNA to assess the in vivo infection history of CMV-specific CD4+ T cells. We found that CMV-specific CD4+ T cells which produced MIP-1beta contained 10 times less Gag DNA than did those which failed to produce MIP-1beta. These data suggest that CD4+ T cells which produce MIP-1alpha and MIP-1beta bind these chemokines in an autocrine fashion which decreases the risk of in vivo HIV infection.
Topics: Adult; CD4-Positive T-Lymphocytes; Cells, Cultured; Chemokine CCL3; Chemokine CCL4; Chemokines, CC; Cytomegalovirus; Cytomegalovirus Infections; Female; Flow Cytometry; HIV Infections; Humans; Male; Middle Aged; Phosphoproteins; Receptors, CCR5; Viral Matrix Proteins; gag Gene Products, Human Immunodeficiency Virus
PubMed: 19876388
DOI: 10.1371/journal.ppat.1000646 -
Journal of Acquired Immune Deficiency... Jul 1999To study the susceptibility to infection by different strains of HIV-1 viruses and the roles of chemokines (macrophage inflammatory protein-1alpha [MIP-1alpha],...
OBJECTIVES
To study the susceptibility to infection by different strains of HIV-1 viruses and the roles of chemokines (macrophage inflammatory protein-1alpha [MIP-1alpha], MIP-1beta, and regulated-on-activation-T-expressed-and-secreted [RANTES]) in CD34+ stem cells maturing into dendritic cells (DC).
DESIGN
It has been controversial whether CD34+ stem cells are susceptible to HIV-1 infection and whether high levels of beta-chemokines are beneficial for suppressing HIV-1 infection during DC maturation. These questions were addressed using different strains of HIV-1 and CD34+ stem cells taken from cord blood and cultured with granulocyte-macrophage colony stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha) to generate mature DC.
METHODS
CD34+ stem cells were exposed with M-tropic virus Ba-L or T-tropic viruses IIIB or Rut at day 1. Beta-chemokines were added to some cells before the virus and kept throughout the culture. Virus replication was measured throughout the maturation of these cells into CD1a+ DC and CD1a- CD14+ cells using enzyme-linked immunosorbent assay (ELISA) for p24, nested polymerase chain reaction (PCR) for env and intracellular p24 detection by flow cytometry.
RESULTS
First, CD34+ stem cells acquired or were infected by live virus because maturing cells showed infection by both M- and T-tropic viruses. Second, the viruses replicated actively during the maturation of CD34+ stem cells toward CD1a+ DC and CD1a- CD14+ cells. Third, beta-chemokines suppressed infection by M-tropic virus Ba-L. And finally, beta-chemokines enhanced infection by T-tropic viruses IIIB and Rut.
CONCLUSIONS
In addition to the initial anti-M-tropic virus effect by beta-chemokines, selective pressure on viruses may also result because of an increase in susceptibility to T-tropic virus. Caution should be taken when evaluating the effect of beta-chemokine receptor agonists in AIDS therapy.
Topics: Antigens, CD34; Cell Count; Chemokine CCL3; Chemokine CCL4; Chemokines, CC; Dendritic Cells; Gene Expression; HIV-1; Hematopoietic Stem Cells; Humans; Macrophage Inflammatory Proteins; Macrophages; Receptors, CCR5; Receptors, CXCR4; T-Lymphocytes
PubMed: 10421240
DOI: 10.1097/00126334-199907010-00001 -
Clinical and Experimental Immunology Nov 2002
Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Chemokines, CC; HIV Infections; HIV-1; Humans
PubMed: 12390302
DOI: 10.1046/j.1365-2249.2002.02010.x -
Journal of Leukocyte Biology Nov 1997Allergic inflammation is characterized by the tissue accumulation and activation of leukocytes rich in eosinophils. During these responses, there is marked induction of... (Review)
Review
Allergic inflammation is characterized by the tissue accumulation and activation of leukocytes rich in eosinophils. During these responses, there is marked induction of specific chemokines that are involved in regulating the recruitment and activation of these inflammatory cells. A subfamily of CC (or beta) chemokines composed of macrophage chemoattractant proteins (MCP) and eotaxin have emerged as cytokines involved in the recruitment and activation of the cells seen in allergic reactions. We now show that these chemokines are strikingly related in chromosomal location, gene structure, primary protein sequence, biological activity, and receptor usage. We also show that these chemokines are differentially regulated in human and animal models of allergic disease and perform distinct roles in vivo. We propose that this subfamily of chemokines plays a fundamental role in the development of allergic responses.
Topics: Amino Acid Sequence; Animals; Chemokine CCL11; Chemokines, CC; Cytokines; Humans; Hypersensitivity; Inflammation; Mice; Molecular Sequence Data; Monocyte Chemoattractant Proteins; Sequence Homology, Amino Acid
PubMed: 9365117
DOI: 10.1002/jlb.62.5.620 -
Glia Jan 2002Chemokines play specific roles in directing the recruitment of leukocyte subsets into inflammatory foci within the central nervous system (CNS). The involvement of these...
Chemokines play specific roles in directing the recruitment of leukocyte subsets into inflammatory foci within the central nervous system (CNS). The involvement of these cytokines as mediators of inflammation is widely accepted. Recently, it has become evident that cells of the CNS (astrocytes, microglia, and neurons) not only synthesize, but also respond functionally or chemotactically to chemokines. We previously reported developmental events associated with colonization of the human fetal CNS by mononuclear phagocytes (microglial precursors), which essentially takes place within the first two trimesters of life. As part of the array of signals driving colonization, we noted specific anatomical distribution of chemokines and chemokine receptors expressed during this period. In order to further characterize expression of these molecules, we have isolated and cultured material from human fetal CNS. We demonstrate that unstimulated subconfluent human fetal glial cultures express high levels of CCR2 and CXCR4 receptors in cytoplasmic vesicles. Type I astrocytes, and associated ameboid microglia in particular, express high levels of surface and cytoplasmic CXCR4. Of the chemokines tested (MIP-1alpha, MIP-1beta, MCP-1, MCP-3, RANTES, SDF-1, IL-8, IP-10), only MIP-1alpha, detected specifically on microglia, was expressed both constitutively and consistently. Low variable levels of MCP-1, MIP-1alpha, and RANTES were also noted in unstimulated glial cultures. Recombinant human chemokines rhMCP-1 and rhMIP-1alpha also displayed proliferative effects on glial cultures at [10 ng/ml], but displayed variable effects on CCR2 levels on these cells. rhMCP-1 specifically upregulated CCR2 expression on cultured glia at [50 ng/ml]. It is gradually becoming evident that chemokines are important in embryonic development. The observation that human fetal glial cells and their progenitors express specific receptors for chemokines and can be stimulated to produce MCP-1, as well as proliferate in response to chemokines, supports a role for these cytokines as regulatory factors during development.
Topics: Astrocytes; Cell Division; Cell Movement; Cells, Cultured; Central Nervous System; Chemokine CCL2; Chemokine CCL3; Chemokine CCL4; Chemokines, CC; Colony-Stimulating Factors; Fetus; Humans; Immunohistochemistry; Lipopolysaccharides; Macrophage Inflammatory Proteins; Microglia; Receptors, CCR2; Receptors, CXCR4; Receptors, Chemokine; Recombinant Proteins
PubMed: 11746784
DOI: 10.1002/glia.1128 -
Current Biology : CB Mar 1998A major advance in understanding human immunodeficiency virus (HIV) biology was the discovery that the beta-chemokines MIP-1 alpha (macrophage inflammatory protein-1...
A major advance in understanding human immunodeficiency virus (HIV) biology was the discovery that the beta-chemokines MIP-1 alpha (macrophage inflammatory protein-1 alpha), MIP-1 beta (macrophage inflammatory protein-1 beta) and RANTES (regulated on activation, normal T-cell expressed and secreted) inhibit entry of HIV-1 into CD4+ cells by blocking the critical interaction between the CCR5 coreceptor and the V3 domain of the viral envelope glycoprotein gp120 [1,2]. CD8+ lymphocytes are a major source of beta-chemokines [3], but the stimulus for chemokine release has not been well defined. Here, we have shown that engagement of CD8+ cytotoxic T lymphocytes (CTLs) with HIV-1-encoded human leukocyte antigen (HLA) class I-restricted peptide antigens caused rapid and specific release of these beta-chemokines. This release paralleled cytolytic activity and could be attenuated by naturally occurring amino acid variation within the HLA class I-restricted peptide sequence. Epitope variants that bound to appropriate HLA class I molecules but failed to stimulate cytolytic activity in CTLs also failed to stimulate chemokine release. We conclude that signalling through the T-cell receptor (TCR) following binding of antigen results in beta-chemokine release from CTLs in addition to cytolytic activity, and that both responses can be abolished by epitope mutation. These results suggest that antigenic variation within HIV-1 might not only allow the host cell to escape lysis, but might also contribute to the propagation of infection by failing to activate beta-chemokine-mediated inhibition of HIV-1 entry.
Topics: Chemokine CCL4; Chemokine CCL5; Chemokines, CC; Chromatography, High Pressure Liquid; Epitopes, T-Lymphocyte; HIV-1; HLA Antigens; Humans; Macrophage Inflammatory Proteins; Peptides; Polymerase Chain Reaction; T-Lymphocytes, Cytotoxic
PubMed: 9512422
DOI: 10.1016/s0960-9822(98)70138-1 -
Journal of Leukocyte Biology Sep 2000Macrophage-derived chemokine (MDC) is a CC chemokine paradigmatic of emerging aspects of chemokine immunobiology. It is constitutively expressed, yet microbial products... (Review)
Review
Macrophage-derived chemokine (MDC) is a CC chemokine paradigmatic of emerging aspects of chemokine immunobiology. It is constitutively expressed, yet microbial products and cytokines regulate its expression with divergent effects of type II (IL-4 and IL-13) and type I (interferon) cytokines. Processing of the mature protein by dipeptidyl peptidase IV/CD26 provides a further level of regulation. It acts on diverse cellular targets including dendritic cells (DC), NK cells, and T cell subsets. Among these, MDC is a potent attractant for CCR4 expressing polarized Th2 and Tc2 cells, and evidence is consistent with a role of this chemokine as an amplification loop of polarized type II responses. Emerging indications on the involvement of MDC in diverse pathologies, ranging from allergic reactions to HIV infection and neoplasia, are discussed.
Topics: Chemokine CCL22; Chemokines, CC; Humans; Macrophages
PubMed: 10985257
DOI: No ID Found -
International Journal of Infectious... Sep 2010Despite advances in neonatal care, sepsis remains a threat, in particular for premature neonates, due to immature immunologic defense. Deficient chemotaxis, an essential...
BACKGROUND
Despite advances in neonatal care, sepsis remains a threat, in particular for premature neonates, due to immature immunologic defense. Deficient chemotaxis, an essential process in the host response to pathogens, may contribute to this vulnerability. In this study we investigated chemokine expression in septic premature and term neonates.
METHODS
Seventy-one neonates with signs and symptoms suggestive of systemic infection, requiring full sepsis evaluation and treatment, formed the study group; 58 neonates without sepsis served as the control group. Serum concentrations of two α-chemokines (GRO-α and ENA-78) and two β-chemokines (RANTES and MIP-1α) were measured at day 0 and day 3-5 of infection in the study group, and on the day of inclusion in the study in the control group.
RESULTS
During infection, serum levels of GRO-α in the study group were higher and serum levels of RANTES were lower as compared to those of the control group (p<0.001 and p<0.001, respectively). Furthermore, levels of GRO-α were higher and levels of RANTES were lower on day 0 as compared to levels on day 3-5 (p<0.001 and p<0.001, respectively). Chemokine serum concentrations on day 3-5 in the study group did not differ significantly as compared to those of the control group. Term and preterm infants seemed to respond similarly regarding chemokine expression. No significant differences were found in serum levels of MIP-1α and ENA-78.
CONCLUSIONS
Our findings suggest up-regulation of GRO-α and down-regulation of RANTES at the onset of a septic episode, similar to the response pattern observed in septic adults. Both term and preterm neonates appear to have the potential to elicit a chemotactic response to infection.
Topics: Chemokine CCL5; Chemokine CXCL1; Chemokines, CC; Chemokines, CXC; Down-Regulation; Humans; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Infant, Premature, Diseases; Sepsis; Up-Regulation
PubMed: 20685145
DOI: 10.1016/j.ijid.2010.03.015 -
Neuropathology and Applied Neurobiology Feb 2005The idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterized by chronic lymphocytic and macrophagic infiltration in muscle. Because the...
The idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterized by chronic lymphocytic and macrophagic infiltration in muscle. Because the mechanism for recruitment of these cells probably involves chemokines, we focused on the study of the expression pattern of some beta chemokines and receptors because it may provide a basis for selective immunotherapy. The expression of CCL3 (MIP-1alpha), CCL4 (MIP-1beta), CCL5 (RANTES) and their main receptors (CCR1 and CCR5) was studied by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry in a series of 16 IIM and five controls (four normal muscles and one tonsil). Except for CCL5, strong expression was observed by RT-PCR with all molecules in all IIM subtypes in comparison to control muscle. Immunohistochemistry revealed diffuse CCL4 expression in all vessels in dermatomyositis. In both polymyositis and sporadic inclusion body myositis (s-IBM) it was restricted to vessels in the vicinity of inflammatory exudates. CCL5 expression was low, restricted to a few inflammatory cells in all IIM; CCR1 expression was mainly restricted to macrophages and s-IBM endothelial cells, whereas CCR5 was localized in inflammatory cells invading non-necrotic muscle fibres. Expressions of both receptors were also recorded in few muscle fibres. In conclusion, the upregulation of beta chemokines and receptors in IIM and their differential expression by various cells may contribute to chronic inflammation and to the peculiar distribution of inflammatory exudates in these diseases.
Topics: Adolescent; Adult; Aged; Chemokines, CC; Female; Humans; Immunohistochemistry; Male; Middle Aged; Muscle, Skeletal; Myositis; Receptors, Chemokine; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 15634233
DOI: 10.1111/j.1365-2990.2004.00591.x