UNIPROT:P10145 - FACTA Search

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Query: UNIPROT:P10145 (IL-8)
23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infectious complications represent a substantial cause of morbidity and mortality in children undergoing therapy for acute myeloid leukemia (AML). Since it has been shown that alterations in innate immune pathways contribute to the risk for serious infections, we analyzed well-characterized variants in innate immune genes (TNF, IL6, IL8, MPO, CHIT, FCGR2A, TLR2, and TLR4) to determine their possible contribution to infectious complications during therapy for pediatric AML. The study population consisted of 168 North European Caucasian children enrolled on the clinical trial AML-BFM 93. We found an association between Gram-negative bacterial infection and common, functional variants in two genes, IL6 and CHIT. The risk for infection was significantly higher in children with the G allele in the IL6 promoter at -174 bp (P=0.026) and in patients with the H allele of CHIT (P=0.033). The promoter variant in IL6 has been shown to increase expression while the H allele disrupts both function and circulating levels. Our data suggest that variant alleles of both IL6 and CHIT could influence susceptibility to infection with Gram-negative bacteria in children undergoing therapy for AML. Follow-up studies, namely replication association studies and in vitro investigation of these common polymorphisms, are warranted to confirm these observations.
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PMID:Common genetic variants in the interleukin-6 and chitotriosidase genes are associated with the risk for serious infection in children undergoing therapy for acute myeloid leukemia. 1610 86

Knowledge about the origin and identity of the microbial products recognized by the innate immune system is important for understanding the pathogenesis of inflammatory diseases. We investigated the potential role of Salmonella enterica serotype Typhimurium fimbriae as pathogen-associated molecular patterns (PAMPs) that may stimulate innate pathways of inflammation. We screened a panel of 11 mutants, each carrying a deletion of a different fimbrial operon, for their enteropathogenicity using the calf model of human gastroenteritis. One mutant (csgBA) was attenuated in its ability to elicit fluid accumulation and GROalpha mRNA expression in bovine ligated ileal loops. The mechanism by which thin curled fimbriae encoded by the csg genes contribute to inflammation was further investigated using tissue culture. The S. Typhimurium csgBA mutant induced significantly less IL-8 production than the wild type in human macrophage-like cells. Purified thin curled fimbriae induced IL-8 expression in human embryonic kidney (HEK293) cells transfected with Toll-like receptor (TLR) 2/CD14 but not in cells transfected with TLR5, TLR4/MD2/CD14 or TLR11. Fusion proteins between the major fimbrial subunit of thin curled fimbriae (CsgA) and glutathione-S-transferase (GST) elicited IL-8 production in HEK293 cells transfected with TLR2/CD14. Proteinase K treatment abrogated IL-8 production elicited in these cells by GST-CsgA, but not by synthetic lipoprotein. GST-CsgA elicited more IL-6 production than GST in bone marrow-derived macrophages from TLR2+/+ mice, while there was no difference in IL-6 secretion between GST-CsgA and GST in macrophages from TLR2-/- mice. These data suggested that CsgA is a PAMP that is recognized by TLR2.
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PMID:CsgA is a pathogen-associated molecular pattern of Salmonella enterica serotype Typhimurium that is recognized by Toll-like receptor 2. 1616 66

Despite recent identification of specific pattern recognition receptors (PRR) for distinct microbial structures, data indicating their relevance in human infectious diseases are limited. We determined the expression levels of the Toll-like receptor (TLR)2 and TLR4 by flow cytometry on granulocytes and monocytes of healthy neonates compared with healthy adults. The basal expression of TLR2 was only slightly lower in neonatal phagocytes, whereas no differences could be detected for TLR4. Analyzing neonates with sepsis, we found an impressive up-regulation of TLR2 on blood phagocytes already at initial presentation of symptoms. Comparison with C-reactive protein, IL-8, and IL-6 suggested that TLR2 expression on monocytes is comparably valuable as an early sepsis marker. TLR2 was differentially regulated during neonatal sepsis, showing a constant up-regulation on monocytes but only a transient increase on granulocytes. Surprisingly, TLR4 showed no remarkable changes. Our results revealed a mild deficiency of TLR2 expression in newborns and demonstrated a differential expression of TLR2 but not TLR4 in the course of neonatal sepsis, which could reflect specific inflammatory responses to distinct pathogens. The definition of TLR expression patterns might open a new field of therapeutic targets for neonatal sepsis.
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PMID:Expression of toll-like receptors in neonatal sepsis. 1618 89

Acne vulgaris is a common disorder that affects 40-50 million people in the USA alone. The pathogenesis of acne is multifactorial, including hormonal, microbiological and immunological mechanisms. One of the factors that contributes to the pathogenesis of acne is Propionibacterium acnes; yet, the molecular mechanism by which P. acnes induces inflammation is not known. Recent studies have demonstrated that microbial agents trigger cytokine responses via Toll-like receptors (TLRs). TLRs are pattern recognition receptors that recognize pathogen-associated molecular patterns conserved among microorganisms and elicit immune responses. We investigated whether TLR2 mediates P. acnes-induced cytokine production in acne. Using transfectant cells we found that TLR2 was sufficient for NF-kappaB activation in response to P. acnes. In addition, peritoneal macrophages from wild-type, TLR6 knockout and TLR1 knockout mice, but not TLR2 knockout mice, produced IL-6 in response to P. acnes.P. acnes induced activation of IL-12 and IL-8 production by primary human monocytes, and this cytokine production was inhibited by anti-TLR2-blocking antibody. Finally, in acne lesions, TLR2 was expressed on the cell surface of macrophages surrounding pilosebaceous follicles. These data suggest that P. acnes triggers inflammatory cytokine responses in acne by activation of TLR2. As such, TLR2 may provide a novel target for the treatment of this common skin disease.
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PMID:Review of the innate immune response in acne vulgaris: activation of Toll-like receptor 2 in acne triggers inflammatory cytokine responses. 1620 63

Toll-like receptor 2 (TLR2) plays an important role in host defense against bacterial pathogens. Activation of TLR2 signaling not only induces the activation of innate immunity and instructs the development of the acquired immunity but also leads to the detrimental inflammatory responses in inflammatory and infectious diseases. To avoid detrimental inflammatory responses, TLR2 signaling must be tightly regulated. In contrast to the relative known positive regulation of TLR2 signaling, its negative regulation, however, is largely unknown. In addition the distal signaling components that link TLR2 to its downstream signaling pathways have yet to be further defined. In the present study we have provided direct evidence for the negative regulation of TLR2 signaling by the tumor suppressor cylindromatosis (CYLD). We showed that activation of TLR2 signaling by TLR2 ligands including peptidoglycan (PGN), MALP-2, and Pam3CSK4 induces activation of IKKs-IkappaBalpha and MKK3/6-p38 pathways not only by TRAF6 but also by TRAF7, a recently identified TRAF family member. The activation of both pathways leads to the transcription of TNF-alpha, IL-1beta, and IL-8 as well as CYLD. CYLD in turn leads to the inhibition of TRAF6 and TRAF7 likely via a deubiquitination-dependent mechanism. The present studies thus unveil a novel autoregulatory feedback mechanism that negatively controls TLR2-IKKs-IkappaBalpha/MKK3/6-p38-NF-kappaB-dependent induction of immune and inflammatory responses via negatively cross-talking with both TRAF6 and TRAF7. These findings provide novel insights into autoregulation and negative regulation of TLR signaling.
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PMID:The tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for toll-like receptor 2 signaling via negative cross-talk with TRAF6 AND TRAF7. 1623 Mar 48

Previous studies have indicated that peptidoglycan (PepG) from gram-positive bacteria can exert a priming effect on the innate immune response to lipopolysaccharide (LPS) from gram-negative bacteria. Here, we hypothesized that this priming effect may be preceded by enhanced expression of monocyte CD14, Toll-like receptor 2 (TLR2), and TLR4. In an ex vivo whole human blood model, we observed a substantial synergy between LPS and PepG in the release of tumor necrosis factor alpha and interleukin-1beta (IL-1beta) over the 24-h experimental period, whereas the effect on IL-8 and IL-10 release was more time dependent. The priming effect of PepG on cytokine release was preceded by a rapid upregulation of CD14, TLR2, and TLR4 expression on monocytes: at 3 hours there was a twofold increase in CD14 expression (P < 0.03), a fivefold increase in TLR2 expression (P < 0.03), and a twofold increase in TLR4 expression (P < 0.03). CD14 and TLR2 remained upregulated throughout the experimental period following exposure to PepG (P < 0.05). Only a transient upregulation of these monocyte receptors was observed following treatment with LPS or LPS plus PepG. In conclusion, the synergistic effect of LPS and PepG on cytokine release is preceded by a reciprocal upregulation of TLR2 and TLR4 by both bacterial cell wall components.
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PMID:Peptidoglycan of Staphylococcus aureus upregulates monocyte expression of CD14, Toll-like receptor 2 (TLR2), and TLR4 in human blood: possible implications for priming of lipopolysaccharide signaling. 1623 65

We previously showed that human corneal epithelial cells (HCECs) express Toll-like receptors (TLRs), which recognize gram-positive bacteria and respond to Staphylococcus aureus infection by the expression and secretion of proinflammatory cytokines and beta-defensin-2 (hBD2). In this study, we further elucidated the underlying mechanisms regulating hBD-2 expression and its role in innate defense in HCECs in response to S. aureus challenge. Exposure of HUCL cells, a telomerase-immortalized HCEC line, to S. aureus, its exoproducts (1:10 dilution), or synthetic lipopeptide Pam3Cys (10 microg/ml) resulted in the up-regulation of hBD-2, but not hBD1 and hBD3. Similar to HUCL cells, primary HCECs responded to S. aureus-exoproducts and Pam3Cys challenge by expressing hBD2 mRNA and secreting hBD2 into the culture media. Furthermore, these stimuli induced the expression of TLR2 at both mRNA and protein levels. Consistently with its role as a major pattern-recognizing receptor, TLR2 was located at the cell surface by cell surface biotinylation. The treatment of HUCL cells with TLR2 neutralizing antibody resulted in a significant decrease in Pam3Cys-induced hBD2 production as well as IL-6, IL-8, and TNF-alpha secretion. The Pam3Cys-induced hBD2 expression was completely blocked by NF-kappaB inhibitors and partially inhibited by p38 MAP kinase and the JNK inhibitors. Conditioned media derived from HCECs challenged with S. aureus-exoproducts or Pam3Cys exhibited antibacterial activity against S. aureus, Pseudomonas aeruginosa and Escherichia coli. These findings suggest that S. aureus induces hBD2 production through TLR2-mediated pathways in HCECs and that pathogen-challenged, TLR-activated HCECs possess antimicrobial activity. Thus, the epithelium might play a role in innate defense against bacterial infection by directly killing bacteria in the cornea.
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PMID:Toll-like receptor 2-mediated expression of beta-defensin-2 in human corneal epithelial cells. 1624 70

Proinflammatory mediators such as cytokines and NO play pivotal roles in various inflammatory diseases. To combat inflammatory diseases successfully, regulation of proinflammatory mediator production would be a critical process. In the present study, we investigated the in vitro effects of ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), a novel small molecule cytokine production inhibitor, and its mechanism of action. In RAW264.7 cells and mouse peritoneal macrophages, TAK-242 suppressed lipopolysaccharide (LPS)-induced production of NO, tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-6, with 50% inhibitory concentration (IC50) of 1.1 to 11 nM. TAK-242 also suppressed the production of these cytokines from LPS-stimulated human peripheral blood mononuclear cells (PBMCs) at IC50 values from 11 to 33 nM. In addition, the inhibitory effects on the LPS-induced IL-6 and IL-12 production were similar in human PBMCs, monocytes, and macrophages. TAK-242 inhibited mRNA expression of IL-6 and TNF-alpha induced by LPS and interferon-gamma in RAW264.7 cells. The phosphorylation of mitogen-activated protein kinases induced by LPS was also inhibited in a concentration-dependent manner. However, TAK-242 did not antagonize the binding of LPS to the cells. It is noteworthy that TAK-242 suppressed the cytokine production induced by Toll-like receptor (TLR) 4 ligands, but not by ligands for TLR2, -3, and -9. In addition, IL-1beta-induced IL-8 production from human PBMCs was not markedly affected by TAK-242. These data suggest that TAK-242 suppresses the production of multiple cytokines by selectively inhibiting TLR4 intracellular signaling. Finally, TAK-242 is a novel small molecule TLR4 signaling inhibitor and could be a promising therapeutic agent for inflammatory diseases, whose pathogenesis involves TLR4.
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PMID:A novel cyclohexene derivative, ethyl (6R)-6-[N-(2-Chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate (TAK-242), selectively inhibits toll-like receptor 4-mediated cytokine production through suppression of intracellular signaling. 1637 89

Statins were shown to possess immunomodulating properties, but the mechanisms of statin effects on the immune system are poorly understood. We analyzed the influence of statins on professional antigen-presenting dendritic cells (DC). Immature DC were cultivated from monocytes of healthy donors. DC maturation was induced by lipopolysaccharide (LPS; 1 microg/mL). Unstimulated and LPS-stimulated DC were treated with simvastatin or atorvastatin (0.1-1 microM). The expression of CD40, CD83, CD86, and human leukocyte antigen-DR on unstimulated and LPS-stimulated DC was reduced significantly by statins, and the expression of Toll-like receptor 2 (TLR2) and TLR4 on LPS-stimulated DC was enhanced temporarily. Statins caused a significant reduction of endocytosis of fluorescein isothiocyanate-dextran by DC. Statins significantly inhibited the basal secretion of interleukin (IL)-6, IL-8, IL-12, and tumor necrosis factor alpha from unstimulated DC, and their release from LPS-stimulated DC was enhanced. In mixed leukocyte reaction, preincubation of LPS-stimulated DC with statins significantly suppressed their clustering with T cells and their ability to induce T cell proliferation, CD71, and CD25 up-regulation on T cells and the secretion of interferon-gamma and IL-2 from T cells. In conclusion, this study showed that statins suppressed endocytosis, basal secretion of proinflammatory cytokines, and the ability of DC to induce T cell proliferation, activation, and T helper cell type 1 differentiation. However, statin preincubation of LPS-stimulated DC caused a further increase in their secretion of proinflammatory cytokines.
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PMID:Differential effects of statins on relevant functions of human monocyte-derived dendritic cells. 1638 46

Recognition of conserved bacterial structures called pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), may lead to induction of a variety of "early immediate genes" such as chemokines. In the current study, we have in an ex vivo whole blood model studied the induction of the chemokines MIP-1alpha, MCP-1 and IL-8 by various PAMPs. The rate of appearance of Escherichia coli-Lipopolysaccharide (LPS) induced chemokines differed. The production of MIP-1alpha and IL-8 was after 1 h of stimulation significantly higher when compared to unstimulated whole blood, whereas MCP-1 was not significantly elevated until after 3 h. At peak levels the MIP-1alpha concentration induced by E. coli-LPS was 3-5-fold higher than MCP-1 and IL-8. By specific cell depletion, we demonstrated that all three chemokines were mainly produced by monocytes. However, the mRNA results showed that IL-8 was induced in both monocytes and granulocytes. The production of all three chemokines, induced by the E. coli-LPS and Neisseria meningitidis-LPS, was significantly inhibited by antibodies against CD14 and TLR4, implying these receptors to be of importance for the effects of LPS in whole blood. The chemokine production induced by lipoteichoic acid (LTA) and non-mannose-capped lipoarabinomannan (AraLAM) was, however, less efficiently blocked by antibodies against CD14 and TLR2. E. coli-LPS and LTA induced a dose-dependent increase of CD14, TLR2 and TLR4 expression on monocytes in whole blood. These data show that PAMPs may induce chemokine production in whole blood and that antibodies against PRRs inhibit the production to different extent.
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PMID:Chemokine production and pattern recognition receptor (PRR) expression in whole blood stimulated with pathogen-associated molecular patterns (PAMPs). 1640 58

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