Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lyme disease is caused by infection with Borrelia burgdorferi, and is characterized by bacterial persistence and inflammation in a number of host tissues. B. burgdorferi outer surface lipoproteins possess cytokine stimulatory properties that may be responsible for localized inflammation. B. burgdorferi presence is correlated with severity of disease, and the pathology of many tissues, particularly the arthritic joint, is consistent with localized cytokine production. Spirochete invasion of tissues requires interaction with and penetration of vascular endothelium, suggesting endothelial cells may participate in the inflammation of Lyme disease. In this study, outer surface protein A (OspA), a model B. burgdorferi lipoprotein, was found to be a potent stimulant of nuclear factor-kappa B (NF-kappa B) nuclear translocation in human endothelial cells, resulting in nuclear levels similar to those seen in response to known inflammatory mediators. Only the lipid-modified OspA had activity, and activity was not due to contamination with LPS. Nuclear NF-kappa B was detectable within 15 min, suggesting that OspA directly mediates NF-kappa B nuclear translocation. OspA also rapidly up-regulated endothelial cell production of several proteins whose transcription is dependent on NF-kappa B: the cytokine IL-6; the chemokine IL-8; and the adhesion molecules E-selectin, VCAM-1, and ICAM-1. The adhesion molecules were functional, as demonstrated by enhanced binding of neutrophils to OspA-stimulated endothelial monolayers. These data suggest that OspA may initiate synthesis of many proteins essential for localized inflammation via the direct activation of NF-kappa B-dependent transcription. These observations suggest that the interaction of B. burgdorferi lipoproteins with the endothelium may directly induce the inflammation responsible for the symptoms of Lyme disease.
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PMID:Borrelia burgdorferi outer membrane protein A induces nuclear translocation of nuclear factor-kappa B and inflammatory activation in human endothelial cells. 890 37

Chemokines play a central role in the process of leukocyte recruitment to tissues. By their chemotactic activity they guide leukocytes to the site of infection/injury. Chemokines have been suggested to trigger firm adhesion of leukocytes to activated endothelial cells as well as the subsequent diapedesis. For these functions, chemokines produced by EC are particularly well suited. Our experiments with proinflammatory stimuli demonstrate that chemokines are induced in EC by a variety of stimuli including inflammatory cytokines and bacterial structures such as LPS and preparations of B. burgdorferi. The induction of chemokines by all of these agents occurs rapidly and does not require new protein synthesis. Two chemokines, MCP-1 and IL-8, respond to very low doses (0.1-1 U/ml) of proinflammatory cytokines which is important at the beginning of an immune response when soluble inflammatory mediators might still be limiting. The chemokines RANTES, IP-10, and mig show synergistic induction by low doses (1 U/ml) of several inflammatory mediators, which again is important when only limiting amounts of inflammatory stimuli are present. The upregulation of six chemokine genes as well as genes encoding adhesion molecules in two cell types, EC and fibroblasts, by B. burgdorferi suggests that chemokines might play a central role in the regulation of spirochete-induced inflammatory responses and the subsequent immune responses. Recent evidence suggests that T cells with pathogenic potential contribute to chronic inflammation at the late stage of Lyme disease. Therefore, the use of therapeutic agents that block chemokine activity might be useful in treating chronic Lyme arthritis.
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PMID:Regulation of chemokine gene expression in human endothelial cells by proinflammatory cytokines and Borrelia burgdorferi. 899 55

Lyme disease, caused by the tick-borne spirochete Borrelia burgdorferi, is a systemic infection with preponderance for the skin, joints, heart, and nervous system. Inflammatory lesions of target organs are characterized by the presence of spirochetes and inflammatory leukocytes. We have analyzed the potential of B. burgdorferi to induce gene expression of chemokines and adhesion molecules in human endothelial cells, keratinocytes, and fibroblasts. We find induction of the chemokines RANTES (regulated upon activation, normal T cells expressed and secreted), monocyte chemoattractant protein-1, IL-8, gro-alpha, IFN-inducible protein-10, and mig (monokine induced by gamma-IFN), and of the adhesion molecules E-selectin, ICAM-1, and VCAM-1 in endothelial cells and induction of the same chemokines and ICAM-1 in fibroblasts. This is mediated by the lipid moiety of the outer surface lipoprotein A. Induction of chemokine and adhesion molecule genes by B. burgdorferi occurs rapidly and does not require new protein synthesis. Induction is blocked by inhibitors of nuclear factor (NF)-kappa B. We also find that B. burgdorferi induces nuclear translocation of NF-kappa B and a transient increase in the expression of its inhibitor I kappa B-alpha. These findings indicate that B. burgdorferi is a potent inducer of molecules required for leukocyte recruitment to inflammatory foci, and the data suggest that this biologic activity is due to the ability of the spirochetes to activate the pleiotropic transcription factor NF-kappa B.
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PMID:Borrelia burgdorferi activates nuclear factor-kappa B and is a potent inducer of chemokine and adhesion molecule gene expression in endothelial cells and fibroblasts. 912 Feb 85

Borrelia burgdorferi possesses membrane lipoproteins that exhibit stimulatory properties and, consequently, have been implicated in the pathology related to Lyme disease. As CD14 has been shown to mediate signaling by a number of lipid-modified bacterial products, the involvement of CD14 in signaling mediated by two B. burgdorferi lipoproteins, outer surface protein A (OspA) and OspC, was determined. Lipoprotein-mediated induction of nuclear factor-kappaB nuclear translocation and production of IL-8 and IL-6 in HUVEC was enhanced in the presence of serum or soluble rCD14. CD14-specific Abs that block LPS-mediated signaling also inhibited lipoprotein-dependent signaling in HUVEC and neutrophils. The formation of stable complexes between OspA and CD14 was demonstrated by native gel electrophoresis. LPS was found to compete with OspA for binding with CD14, suggesting that LPS and OspA bind similar regions on CD14. The similarity in binding was further supported by the finding that a mutant soluble CD14, lacking the LPS binding site, did not facilitate lipoprotein signaling, nor did it form a complex with OspA. Binding of OspA to CD14 was dependent on the lipid modification, as unlipidated OspA did not form a complex with CD14 or stimulate cells. In contrast, the lipopeptide remaining after proteinase K digestion both formed a complex with CD14 and retained stimulatory properties. These findings indicate that CD14 facilitates bacterial lipoprotein signaling in mammalian cells.
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PMID:The role of CD14 in signaling mediated by outer membrane lipoproteins of Borrelia burgdorferi. 960 51

We estimated serum concentrations of cytokines IL-1, IL-6, IL-8, TNF-alfa and IL-6R of patients with diagnosed Lyme disease treated with beta-lactam antibiotics. Detection of proinflammatory cytokines was performed in ELISA tests. The examination was performed before and after treatment. Comparison with control group stated statistically significant higher concentration of IL-1 and IL-6 before and after treatment. There were no differences in concentration of TNF-alfa, IL-8 and IL-6R. Comparing concentrations of cytokines before and after treatment there was no differences either. Lack of changes in concentration of proinflammatory cytokines during beta-lactam therapy could be explained by too short period of therapy or immunologic background of inflammatory process in Lyme disease which was only initiated by spirochete Borrelia burgdorferi.
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PMID:[Levels of proinflammatory cytokines: IL-1, IL-6, IL-8, TNF-alpha and receptor IL-6R in Lyme borreliosis]. 1068 Apr 54

Chemokines constitute a group of proinflammatory cytokines with a strong chemotactic activity towards different populations of leukocytes. Their role in Lyme borreliosis has not been confirmed, although in vitro studies suggest possibility of chemokine synthesis during Borrelia burgdorferi infection. The aim of present study was to evaluate concentrations of chemokines: interleukin 8 (IL-8) and macrophage inflammatory protein 1 alpha and 1 beta (MIP-1 alpha and MIP-1 beta) in serum of patients with early clinical manifestation of Lyme borreliosis--erythema migrans (EM). Study group consisted of 20 patients with EM, control group of 12 healthy blood donors. Chemokine concentrations were measured with ELISA assays twice: before (examination 1) and after two weeks of antibiotic therapy (examination 2). Mean serum concentrations of IL-8, MIP-1 alpha and MIP-1 beta in examination 1 and of MIP-1 alpha and MIP-1 beta in examination 2 were significantly higher in comparison with control group. Chemokine concentrations were also significantly lower in examination 2 then in examination 1. These results show expression of IL-8, MIP-1 alpha and MIP-1 beta in the course of EM and suggest their role in the inflammatory response to Borrelia burgdorferi infection.
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PMID:[Concentration of macrophage inflammatory proteins MIP-1 alpha and MIP-1 beta and interleukin 8 in erythema migrants]. 1236 60

Innate immunity is important for early defence against borrelia spirochetes and should play a role in the clinical outcome of the infection. In order to study early cytokine responses, in vitro differentiated dendritic cells (DCs) and whole blood cells from 21 patients with different clinical outcomes of Lyme neuroborreliosis were stimulated with live borrelia spirochetes. The borrelia-induced secretion of interleukin (IL)-4, IL-10, IL-12p70, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha in DCs and IL-1beta, IL-6, IL-8, IL-10, IL-12p70, TNF-alpha, regulated upon activation normal T cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and eotaxin in whole blood cells was measured by enzyme-linked immunospot (ELISPOT) and multiplex arrays, respectively. We found increased numbers of TNF-alpha-secreting DCs (P = 0.018) in asymptomatic seropositive individuals compared to patients with subacute neuroborreliosis and seronegative controls. Asymptomatic individuals were also found to have elevated levels of IL-12p70 (P = 0.031) in whole blood cell supernatants compared to seronegative controls. These results are in line with previous experiments using cells of the adaptive immune response, indicating that strong T helper type 1 (Th1) proinflammatory responses might be associated with a successful resolution of Lyme disease.
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PMID:Innate immune responses in Lyme borreliosis: enhanced tumour necrosis factor-alpha and interleukin-12 in asymptomatic individuals in response to live spirochetes. 1595 74

Borrelia burgdorferi and Anaplasma phagocytophilum coinfect and are transmitted by Ixodes species ticks. Clinical indicators suggest that A. phagocytophilum coinfection contributes to the severity, dissemination, and, possibly, sequelae of Lyme disease. Previous in vitro studies showed that spirochete penetration through human brain microvascular endothelial cells of the blood-brain barrier is facilitated by endothelial cell-derived matrix metalloproteases (MMPs). A. phagocytophilum-infected neutrophils continuously release MMPs and other vasoactive biomediators. We examined B. burgdorferi infection of brain microvascular barriers during A. phagocytophilum coinfection and showed that coinfection enhanced reductions in transendothelial electrical resistance and enhanced or synergistically increased production of MMPs (MMP-1, -3, -7, -8, and -9), cytokines (interleukin 6 [IL-6], IL-10, and tumor necrosis factor alpha), and chemokines (IL-8 and macrophage inflammatory protein 1alpha) known to affect vascular permeability and inflammatory responses.
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PMID:Anaplasma phagocytophilum-Borrelia burgdorferi coinfection enhances chemokine, cytokine, and matrix metalloprotease expression by human brain microvascular endothelial cells. 1789 82

Lyme borreliosis is a spirochetal infection caused by the Borrelia burgdorferi sensu lato complex that can proceed towards an inflammatory joint manifestation known as Lyme arthritis. Production of chemokines orchestrating neutrophil infiltration is supposed to be key to early arthritic pathogenesis. Using PMA-differentiated macrophage-like THP-1 (mTHP-1) cells we identified by antibody array methodology or mRNA analysis IL-8, GRO-alpha, NAP-2, and SDF-1alpha as being among those chemokines that are upregulated by bacterial lysates obtained from B. burgdorferi. Based on these observations, we set out to characterize in detail mechanisms mediating IL-8 release in this cellular model. TLR2 blocking antibodies, analysis of p65 translocation, and electromobility-shift analysis revealed activation of the TLR2/NF-kappaB axis by B. burgdorferi. The functional importance of this pathway was substantiated by suppression of IL-8 after inhibition of IkappaB kinase. Notably, MAP kinases, specifically the MEK1/2-ERK1/2 pathway, were essential for IL-8 secretion. Those data were confirmed by using freshly isolated adherent peripheral blood mononuclear cells. On the contrary, B. burgdorferi-induced IL-8 in mTHP-1 was unlikely related to flagellin, alpha3beta1-integrin signaling, lipopolysaccharide, bacterial DNA, NOD1/NOD2 agonists, or to intermediate production of IL-1beta and TNF-alpha. Induction of IL-8 by B. burgdorferi was not due to amplification of constitutive AP-1 DNA-binding activity detectable in mTHP-1 cells. Data presented herein validate that TLR2, particularly on mTHP-1 cells, holds a central position in mediating IL-8 secretion associated with extracellular B. burgdorferi and beyond that suggest inhibition of IkappaB kinase and MEK1/2 kinases as promising pharmacological strategies aiming at IL-8 in early Lyme arthritis.
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PMID:Systematic analysis highlights the key role of TLR2/NF-kappaB/MAP kinase signaling for IL-8 induction by macrophage-like THP-1 cells under influence of Borrelia burgdorferi lysates. 1857 57

Tetracyclines moderate inflammatory responses of various etiologies. We hypothesized that tetracyclines, in addition to their antimicrobial function, could exert control over the inflammation elicited by Borrelia burgdorferi. To model systemic effects, we used the human monocytic cell line THP-1; to model effects in the central nervous system, we used rhesus monkey brain astrocytes and microglia. Cells were stimulated with live or sonicated B. burgdorferi or with the lipoprotein outer surface protein A in the presence of increasing concentrations of doxycycline or minocycline. Both antibiotics significantly reduced the production of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8 in a dose-dependent manner in all cell types. Microarray analyses of the effect of doxycycline on gene transcription in spirochete-stimulated monocytes revealed that the NFKB and CHUK (alias, IKKA) genes were down-regulated. Functionally, phosphorylation of IkappaBalpha and binding of NF-kappaB to target DNA were both reduced in these cells. Our results suggest that tetracyclines may have a dual therapeutic effect in Lyme disease.
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PMID:The antibiotics doxycycline and minocycline inhibit the inflammatory responses to the Lyme disease spirochete Borrelia burgdorferi. 1930 81


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