Key role of chemokines and chemokine receptors in inflammation, immunity, neoplasia, and infectious disease.
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Leukocyte homing is a complex, multistep process involving the coordinated expression of adhesion molecules and certain chemotactic cytokines, termed chemokines. Although chemokines initially burst into the literature as potent inflammatory mediators, it is now clear that they are involved in a variety of processes including lymphocyte maturation, angiogenesis, and tumor growth. Furthermore, a variety of important pathogens manipulate various chemokine/receptor pathways to infect the host and evade the immune system. (+info)
SLC/exodus2/6Ckine/TCA4 induces chemotaxis of hematopoietic progenitor cells: differential activity of ligands of CCR7, CXCR3, or CXCR4 in chemotaxis vs. suppression of progenitor proliferation.
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Chemokines induce chemotaxis of hematopoietic progenitor cells (HPC), and suppress their proliferation. In this study we report that SLC/ Exodus2/6Ckine/TCA4 (hereafter termed SLC) is a chemoattractant for human CD34+ HPC. SLC mainly induces preferential chemotaxis of macrophage progenitors. We examined the chemotactic activity of CXCR3 ligands on CD34+ HPC because it has been reported that SLC is a potential ligand of CXC chemokine receptor, CXCR3, in addition to a CC chemokine receptor, CCR7. It was found that the CXCR3 ligands, MIG and interferon-gamma inducible protein-10 (IP-10), unlike SLC, did not induce chemotaxis of CD34+ HPC. In this regard, CCR7 ligands (SLC and CKbeta-11), but not IP-10 and MIG, induce actin polymerization in CD34+ cells. On the other hand, CCR7 ligands and CXCR3 ligands, but not the CXCR4 ligand SDF-1, showed inhibitory activity for proliferation of myeloid progenitor cells. Our results suggest that SLC is a potential trafficking factor for HPC, and that chemokines that bind CCR7, CXCR4, and CXCR3 have differential biological activities on HPC in terms of suppression and chemotaxis. (+info)
Differential responsiveness to constitutive vs. inducible chemokines of immature and mature mouse dendritic cells.
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Upon exposure to immune or inflammatory stimuli, dendritic cells (DC) migrate from peripheral tissues to lymphoid organs, where they present antigen. The molecular basis for the peculiar trafficking properties of DC is largely unknown. In this study, mouse DC were generated from CD34+ bone marrow precursors and cultured with granulocyte-macrophage-CSF and Flt3 ligand for 9 days. Chemokines active on immature DC include MIP1alpha, RANTES, MIP1beta, MCP-1, MCP-3, and the constitutively expressed SDF1, MDC, and ELC. TNF-alpha-induced DC maturation caused reduction of migration to inducible chemokines (MIP1alpha, RANTES, MIP1beta, MCP-1, and MCP-3) and increased migration to SDF1, MDC, and ELC. Similar results were obtained by CD40 ligation or culture in the presence of bacterial lipopolysaccharide. TNF-alpha down-regulated CC chemokine receptor (CCR)1, CCR2, and CCR5 and up-regulated CCR7 mRNA levels, in agreement with functional data. This study shows that selective responsiveness of mature and immature DC to inducible vs. constitutively produced chemokines can contribute to the regulated trafficking of DC. (+info)
Sensitivity of human immunodeficiency virus infection to various alpha, beta and gamma chemokines.
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Examination of a large panel of chemokines indicates that in addition to RANTES, MIP-1alpha and MIP-1beta, the beta-chemokine MCP-2 and, to a lesser extent, the gamma-chemokine lymphotactin also show anti-human immunodeficiency virus (HIV) activity in cell culture. The amount of chemokine needed to suppress HIV replication by > or = 50% was generally greater (> or = 250 ng/ml) than that required for inhibition of virus infection by RANTES, MIP-1alpha and MIP-1beta. The beta-chemokine MCP-3 was found to enhance the replication of both non-syncytium-inducing (NSI) and syncytium-inducing (SI) viruses at high concentrations (0.5-5 microg/ml). In contrast to a previous report, macrophage-derived chemokine was not found to inhibit HIV replication of either NSI or SI viruses, but at low concentrations enhanced NSI virus replication. When small amounts of RANTES or MCP-2 were added together with high concentrations of non-inhibitory chemokines, the anti-HIV effects were countered. Information on chemokines that affect HIV infection could be useful for future therapeutic strategies. (+info)
Factors produced by activated leukocytes alter renal epithelial cell differentiation.
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The development of tubulointerstitial fibrosis in inflammatory renal diseases has been linked to disease progression to end-stage renal failure. Understanding the interactions of the factors influencing inflammation and activating the fibrotic process, that is, the inflammatory infiltrate and the resident proximal tubular cells, may lead to a determination of the mechanisms that regulate tubulointerstitial fibrosis. We used an in vitro model of human proximal tubule cells that were stimulated with supernatant from activated peripheral blood mononuclear cells (leukocytes) to study the alterations in cellular phenotype, and examined the signaling pathways mediating epithelial-fibroblast like transdifferentiation. Our hypothesis of the proposed sequence of events leading to tubulointerstitial fibrosis is explained. (+info)
Plasmid-mediated resistance to thrombin-induced platelet microbicidal protein in staphylococci: role of the qacA locus.
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Thrombin-induced platelet microbicidal protein 1 (tPMP-1) is a small, cationic peptide released from rabbit platelets following thrombin stimulation. In vitro resistance to this peptide among strains of Staphylococcus aureus correlates with the survival advantage of such strains at sites of endothelial damage in humans as well as in experimental endovascular infections. The mechanisms involved in the phenotypic resistance of S. aureus to tPMP-1 are not fully delineated. The plasmid-encoded staphylococcal gene qacA mediates multidrug resistance to multiple organic cations via a proton motive force-dependent efflux pump. We studied whether the qacA gene might also confer resistance to cationic tPMP-1. Staphylococcal plasmids encoding qacA were found to confer resistance to tPMP-1 in an otherwise susceptible parental strain. Deletions which removed the region containing the qacA gene in the S. aureus multiresistance plasmid pSK1 abolished tPMP-1 resistance. Resistance to tPMP-1 in the qacA-bearing strains was inoculum independent but peptide concentration dependent, with the level of resistance decreasing at higher peptide concentrations for a given inoculum. There was no apparent cross-resistance in qacA-bearing strains to other endogenous cationic antimicrobial peptides which are structurally distinct from tPMP-1, including human neutrophil defensin 1, protamine, or the staphylococcal lantibiotics pep5 and nisin. These data demonstrate that the staphylococcal multidrug resistance gene qacA also mediates in vitro resistance to cationic tPMP-1. (+info)
Acute cellular rejection of human renal tissue by adoptive transfer of allogeneic human peripheral blood mononuclear cells into chimeric rats: sequential gene expression of cytokines, chemokines and cytolytic effector molecules, and their regulation by CTLA-4-Ig.
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T(h)1- and T(h)2-related cytokines (IFN-gamma, IL-2, IL-4, IL-10), beta-chemokines (RANTES, macrophage inflammatory protein-1beta) and their receptor [chemotatic cytokine receptor (CCR) 5], and the cytolytic effector molecule [Fas ligand (FasL)] play an essential role in regulating and co-ordinating acute renal allograft rejection. A chimeric model of acute cellular rejection which involves subcapsular grafting of human renal tissue in the kidneys of immunodeficient rats and subsequent i.p. infusion of allogeneic human peripheral blood mononuclear cells (PBMC) was used to study cellular infiltration patterns and sequential intragraft gene expression of these key inflammatory mediators. We found that while all molecules are expressed within the human renal implant at specific time points following infusion of allogeneic human PBMC, peak mRNA expression of IFN-gamma, IL-2, RANTES and CCR5 is associated with a phase of human mononuclear infiltration and accumulation, prior to graft destruction (induction phase). A short burst of FasL gene expression is found at the end of induction and at the onset of graft deterioration. IL-4 mRNA, which is hardly detectable, and IL-10 mRNA, which appears early and persists throughout follow-up at high levels, both peak after the induction phase with the advent of graft destruction. Furthermore, treatment with CTLA-4-Ig, which hardly affects migration of human effector cells into graft tissue, is associated with a temporary reduction in gene transcript levels for all inflammatory mediators, especially IL-2 and IL-4, reduced apoptosis in the graft and amelioration of tissue injury. Thus, development of acute cellular rejection in our chimeric model involves a co-ordinated pattern of gene expression, in which CTLA-4-Ig promotes its effects by transient inactivation of infiltrating human cells. (+info)
The epithelial cell response to rotavirus infection.
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Rotavirus is the most important worldwide cause of severe gastroenteritis in infants and young children. Intestinal epithelial cells are the principal targets of rotavirus infection, but the response of enterocytes to rotavirus infection is largely unknown. We determined that rotavirus infection of HT-29 intestinal epithelial cells results in prompt activation of NF-kappaB (<2 h), STAT1, and ISG F3 (3 h). Genetically inactivated rotavirus and virus-like particles assembled from baculovirus-expressed viral proteins also activated NF-kappaB. Rotavirus infection of HT-29 cells induced mRNA for several C-C and C-X-C chemokines as well as IFNs and GM-CSF. Mice infected with simian rotavirus or murine rotavirus responded similarly with the enhanced expression of a profile of C-C and C-X-C chemokines. The rotavirus-stimulated increase in chemokine mRNA was undiminished in mice lacking mast cells or lymphocytes. Rotavirus induced chemokines only in mice <15 days of age despite documented infection in older mice. Macrophage inflammatory protein-1beta and IFN-stimulated protein 10 mRNA responses occurred, but were reduced in p50-/- mice. Macrophage inflammatory protein-1beta expression during rotavirus infection localized to the intestinal epithelial cell in murine intestine. These results show that the intestinal epithelial cell is an active component of the host response to rotavirus infection. (+info)