Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Administration of antiasthmatic drugs in the form of inhalation particles may alter the cytokine network in the airways, independently of their pharmacological actions. Changes induced by drugs not well tolerated may potentially contribute to the immunopathology of the disease, a strongly undesirable effect. In this study, cell viability assays and characterization of the cellular profile of cytokines and chemokines were performed in order to investigate the response of human bronchoalveolar macrophages and bronchial epithelial cells in culture to inhalation particles of the cyclosporine derivative IMM 125. Interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and IL-8 were assayed by enzyme-linked immunosorbent assay (ELISA) in the supernatants of bronchoalveolar macrophages, and RANTES, granulocyte--macrophage colony-stimulating factor (GM-CSF), and IL-8 in those of bronchial epithelial cells. Cells were studied both under basal and stimulated conditions (lipopolysaccharide and TNFalpha were used for activating macrophages and epithelial cells, respectively). The immunosuppressant FK 506 and the glucocorticoid Budesonide served as comparison. IMM 125 did not affect cell viability (except at high concentrations and long time periods). Moreover, IMM 125 did not induce an increase in the secretion of any of the cytokines and chemokines measured with respect to nontreated cells, except for a slight increase in IL-8, an effect that was also observed for FK 506, Budesonide, and inert latex particles, and was therefore regarded as nonspecific. Furthermore, IMM 125 significantly decreased the secretion of TNFalpha, IL-1beta by macrophages, and GM-CSF by epithelial cells, suggesting an antiinflammatory potential. In conclusion, the present in vitro results point to a good tolerance of human airways to IMM 125 inhalation particles.
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PMID:Cytokine profile of human bronchoalveolar macrophages and bronchial epithelial cells in response to inhalation particles of the cyclosporine derivative IMM 125. 1047 42

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.
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PMID:Differential responsiveness to constitutive vs. inducible chemokines of immature and mature mouse dendritic cells. 1049 20

Earlier studies have supported a significant role for cocaine in the susceptibility to and the progression of human immunodeficiency virus type 1 (HIV-1) infection. Recently, several unique HIV-1 entry coreceptors (e.g., CCR5 and CCR3) and a trio of HIV-1-specific suppressor chemokines, namely, RANTES (regulated-upon-activation T expressed and secreted), macrophage inflammatory protein 1alpha (MIP-1alpha) and MIP-1beta, were identified. Although cocaine has been linked to the immunopathogenesis of HIV-1 infection, the corresponding cellular and molecular mechanism(s) have not been well defined. We hypothesize that cocaine mediates these pathologic effects through the downregulation of HIV-1-suppressing chemokines and/or upregulating HIV-1 entry coreceptors in HIV-1-infected subjects, resulting in disease progression to AIDS. Our results show that cocaine selectively downregulates endogenous MIP-1beta secretion by normal peripheral blood mononuclear cells (PBMC), while cocaine did not affect the MIP-1beta production by PBMC from AIDS patients. Cocaine also selectively suppresses lipopolysaccharide-induced MIP-1beta production by PBMC from HIV-infected patients. Further, cocaine significantly downregulates endogenous MIP-1beta gene expression, while it upregulates HIV-1 entry coreceptor CCR5 by normal PBMC. These studies suggests a role for cocaine as a cofactor in the pathogenesis of HIV infection and support the premise that cocaine increases susceptibility to and progression of HIV-1 infection by inhibiting the synthesis of HIV-1 protective chemokines and/or upregulating the HIV-1 entry coreceptor, CCR5.
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PMID:Cocaine differentially modulates chemokine production by mononuclear cells from normal donors and human immunodeficiency virus type 1-infected patients. 1061 85

RANTES (regulated upon activation, normal T cell expressed and secreted), which is a potent chemoattractant for eosinophils, lymphocytes, and monocytes, was recently detected in the human endometrium. The effects of modulators of endometrial function, including lipopolysaccharide (LPS), tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-4 and interferon-gamma (IFN-gamma), on the production of RANTES by endometrial stromal cells (ESC) were examined by an enzyme-linked immunosorbent assay and Northern blot analysis. The concentration of RANTES in the culture media of non-stimulated ESC was below the level of detection. The concentration of RANTES was increased by the addition of TNF-alpha, IL-1beta and LPS. IFN-gamma synergistically enhanced the TNF-alpha- and LPS-induced RANTES expression, but had no effect on the IL-1beta-induced RANTES expression. The TNF-alpha-induced production of RANTES by ESC was inhibited by IL-4. The transcription of RANTES in ESC was also stimulated by TNF-alpha, IL-1beta and LPS in a dose-dependent manner. It is suggested that the LPS and cytokines secreted by the maternal decidual tissue and the developing embryo may regulate the production of RANTES by ESC. The modulation of RANTES concentration in the local environment may contribute to the pathophysiological processes of human reproduction by regulating the immunological reaction at the fetal-maternal interface.
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PMID:Effects of lipopolysaccharide and cytokines on production of RANTES by cultured human endometrial stromal cells. 1069 72

This work tests the hypotheses that Kupffer cells are a major source of CC-chemokines (MIP-1alpha, MCP-1, RANTES) during acute endotoxemia and that acute ethanol intoxication modulates Escherichia coli lipopolysaccharide (LPS, 1 mg/Kg, i.v.)-induced chemokine release in the rat. LPS stimulated the release of CC-chemokines into the circulation, hepatic sequestration of leukocytes and liver injury. LPS-induced serum chemokines peaked at 1-3 h and could not be detected at 24-h posttreatment. Splenectomy significantly suppressed LPS-induced RANTES release, but not MIP-1alpha and MCP-1. Kupffer cell depletion by gadolinium chloride or acute ethanol intoxication significantly attenuated LPS-induced CC-chemokine release and hepatic injury. Hepatic sequestration of leukocytes during endotoxemia was also suppressed by acute ethanol. LPS downregulated the expression of MIP-1alpha and MCP-1 mRNAs and upregulated RANTES mRNA in Kupffer cells at 3-h post endotoxin. The expression of mRNAs was further suppressed in ethanol plus the LPS-treated group. Ethanol also suppressed the LPS-mediated priming of Kupffer cells for enhanced CC-chemokine release in vitro. Ethanol alone significantly upregulated the expression of CC-chemokine mRNA, and primed the Kupffer cells for enhanced RANTES release. CC-chemokine release and mRNA expression in hepatic sinusoidal endothelial cells were not significantly altered by ethanol, except for MCP-1 release. These data show that acute ethanol may be beneficial in tissue injury during acute endotoxemia.
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PMID:Acute alcohol intoxication and gadolinium chloride attenuate endotoxin-induced release of CC chemokines in the rat. 1071 99

The chemokine RANTES is produced by a variety of tissues, including cells of the monocyte/macrophage lineage. RANTES expression is rapidly and transiently up-regulated in primary monocytes and the monocytic cell line Mono Mac 6 in response to stimulation by the bacterial product lipopolysaccharide (LPS). Transient transfection of Mono Mac 6 cells with RANTES reporter-promoter deletion constructs, in conjunction with DNase I footprinting and heterologous reporter gene assays, allowed identification of an LPS-responsive region within the RANTES promoter. Electrophoretic mobility shift assays (EMSA), methylation interference and EMSA supershift experiments were used to characterize sequences and transcription factors responsible for this LPS inducibility. The region, termed RANTES site G [R(G)], contains consensus sites for Ets and CRE/AP-1-like elements. Site-directed mutagenesis of the Ets site resulted in a loss of only 15 % of promoter activity, while mutation of the CRE/AP-1 site led to a loss of 40 % of LPS-induced promoter activity. The Ets site constitutively binds the Ets family member PU.1. LPS stimulation leads to an induction of ATF-3 and JunD factor binding to the CRE/AP-1 site. Thus, LPS induction of RANTES transcription is mediated, in part, through the activation and selective binding of ATF and Jun nuclear factors to the R(G) promoter module.
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PMID:ATF and Jun transcription factors, acting through an Ets/CRE promoter module, mediate lipopolysaccharide inducibility of the chemokine RANTES in monocytic Mono Mac 6 cells. 1076 Jul 99

Dendritic cells (DC) are highly-specialized antigen-presenting cells (APC), that initiate and modulate immune responses. Their specialized migratory and tissue-homing properties are regulated by small molecular weight proteins (chemokines) that govern leukocyte migration and activation. Little is known about the capacity of liver DC to produce or respond to chemokines. Here we examined chemokine and chemokine receptor (CR) gene expression in both immature DC progenitors (DCp) and comparatively mature DC generated from mouse liver. Factors affecting production of the chemokine macrophage inflammatory protein (MIP)-1alpha, and the influence of MIP-1alpha on liver DC migration were also investigated. Dendritic cells were propagated in response to granulocyte-macrophage colony stimulating factor (GM-CSF) +/- interleukin (IL)-4 from bone marrow (BM) cells or liver non-parenchymal cells (NPC) isolated from normal mice, or from mice treated with the hematopoietic growth factor Flt3 ligand (FL). Their phenotype and allostimulatory function were assessed by monoclonal antibody (mAb) staining and flow cytometry, and by the capacity to induce mixed leukocyte reactions, respectively. Specific chemokine and CR gene expression was studied using the RNase protection assay (RPA). Production of MIP-1alpha was determined by enzyme-linked immunoabsorbent assay (ELISA), and the migratory activity of liver DC induced by MIP-1alpha quantitated using microchemotaxis chambers. Like DC generated simultaneously from BM, liver-derived DC expressed mRNA for a variety of CC and CXC chemokines. RANTES (regulated upon activation, normal T cell expressed and secreted) transcripts were the most strongly expressed. Gene transcripts for the receptor CCR1, that binds RANTES and MIP-1alpha were also readily detected, as was CCR2, the receptor for the monocyte chemotactic proteins (MCP)1-4. No major differences in chemokine or CR mRNA expression were detected between immature and more mature liver DC. MIP-1alpha production by liver-derived DC was stimulated by bacterial lipopolysaccharide (LPS), and high levels were also detected in co-cultures of hepatic DC and allogeneic T cells. Chemotactic migration of liver-derived DC was stimulated by MIP-1alpha. Thus, liver-derived DC express mRNA for several CC and CXC chemokines and their receptors that may play key roles in the regulation of hepatic inflammatory responses. Production of MIP-1alpha by liver DC, and their migratory responses to this chemokine, suggest that MIP-1alpha and other chemokines may play significant roles in the regulation of liver DC function and in interactions of liver DC with other leukocytes, under normal and inflammatory conditions.
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PMID:Chemokine and chemokine receptor expression by liver-derived dendritic cells: MIP-1alpha production is induced by bacterial lipopolysaccharide and interaction with allogeneic T cells. 1083 7

Regulation by the p38 mitogen-activated protein (MAP) kinase signaling pathway of monocytic inflammatory functions was evaluated using L-790,070, a potent and selective inhibitor of p38 MAP kinase. Three major functions of monocytes were investigated: differentiation, chemotaxis, and phagocytosis. L-790,070 inhibited serum-induced monocyte differentiation with an IC50 of 0.5 nM. Monocyte chemotaxis induced by RANTES, macrophage inflammatory protein-1alpha (MIP-1alpha), monocyte chemotactic protein- (MCP-1), and fMLP were all sensitive to L-790,070. When titrated, L-790,070 inhibited MCP-1-induced chemotaxis in a concentration-dependent manner with an IC50 of 0.3 nM. However, the ability of serum-derived macrophages to phagocytose apoptotic neutrophils was unaffected by L-790,070. The concentration with which L-790,070 inhibited both differentiation and chemotaxis was similar to that necessary to inhibit p38 MAP kinase activation of MAPKAP kinase (0.3 nM) in response to stimulation by lipopolysaccharide. Therefore, the data in this report suggest that the mechanism by which L-790,070 blocked monocyte differentiation and prevented chemotaxis was by inhibiting p38 MAP kinase activity.
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PMID:Serum-induced monocyte differentiation and monocyte chemotaxis are regulated by the p38 MAP kinase signal transduction pathway. 1085 61

Bacterial lipopolysaccharide (LPS) has been shown to induce a wide variety of pro-inflammatory cytokines and chemokines. An initial challenge with minute amounts of LPS causes tolerance to later LPS effects which is characterized by a much lower or abrogated release of pro-inflammatory cytokines. To explore the relationship between the production of chemokines and the induction of LPS tolerance, we pretreated human monocytes with increasing LPS doses and thereafter restimulated with LPS. The re-expression of the CC chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and RANTES was substantially suppressed after pre-incubation with low LPS doses. In striking contrast, the re-expression of neutrophil-attracting IL-8 and melanoma growth stimulatory activity-alpha and of the monocyte-attracting monocyte chemotactic protein-1 remained high and was, in part, initially increased after restimulation with LPS. The corresponding gene expression pattern as determined by Northern blot analyses correlated closely with the release of chemokines and cytokines. Thus, a basic set of chemotactic mediators that are still produced by otherwise LPS-desensitized monocytes/macrophages may ensure the continuing recruitment of monocytes and neutrophils into an inflammatory process caused by gram-negative bacteria.
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PMID:Differential desensitization of lipopolysaccharide-inducible chemokine gene expression in human monocytes and macrophages. 1089 91

Cholera toxin (CT) is a potent mucosal adjuvant that amplifies B and T cell responses to mucosally co-administered antigens, stimulating predominant Th2-type responses. However, little is known about the mechanism of adjuvanticity of CT and on the influence this toxin may have on Th2 cell development during the priming of an immune response. We analyzed the effect of CT on dendritic cells (DC), which are responsible for the priming of immune responses at the systemic as well as at the mucosal level. We found that CT induces phenotypic and functional maturation of blood monocyte-derived DC. Indeed, CT-treated DC up-regulate expression of HLA-DR molecules, B7. 1 and B7.2 co-stimulatory molecules, and are able to prime naive CD4(+)CD45RA(+) T cells in vitro, driving their polarization towards the Th2 phenotype. Furthermore, CT-matured DC express functional chemokine receptors CCR7 and CXCR4 which may render them responsive to migratory stimuli towards secondary lymphoid organs. Interestingly, the maturation program induced by CT is unique since CT does not induce but rather inhibits cytokine (IL-12p70 and TNF-alpha) and chemokine (RANTES, MIP-1alpha and MIP-1beta) secretion by lipopolysaccharide- or CD40 ligand-activated DC. Our results help to elucidate the mechanism of action of CT as an adjuvant and highlight a new stimulus of bacterial origin that promotes maturation of DC.
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PMID:Cholera toxin induces maturation of human dendritic cells and licences them for Th2 priming. 1094 Sep 31


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