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)

NF-kappaB repressing factor (NRF), a nuclear inhibitor of NF-kappaB, is constitutively expressed and is implicated in the basal silencing of specific NF-kappaB targeting genes, including IFN-beta, IL-8/CXCL8, and iNOS. Little is known about the regulation of NRF and its role in response to stimuli. Airway smooth muscle (ASM) is a rich source of inflammatory mediators that may regulate the development and progression of airway inflammation. We have previously reported that NE activates NF-kappaB in primary human ASM (hASM), leading to induction of TGF-beta1. In this study, we describe that, instead of inducing the NF-kappaB response gene IL-8/CXCL8, NE suppressed IL-8/CXCL8 release and mRNA expression in hASM cells. Transcriptional blockade studies using actinomycin D revealed a similar degradation rate of IL-8/CXCL8 mRNA in the presence or absence of NE, suggesting an involvement at the transcription level. Mechanistically, the NE repressive effect was mediated by inducing NRF, as shown by RT-PCR and Western blotting, which was subsequently recruited to the native IL-8/CXCL8 promoter leading to removal of RNA polymerase II from the promoter, as demonstrated by chromatin immunoprecipitation assays. Knockdown of NRF by small interfering RNA prevented NE-induced suppression of IL-8/CXCL8 expression. In contrast, NE did not induce NRF expression in A549 and Beas-2B cells, where NE only stimulates NF-kappaB activation and IL-8/CXCL8 induction. Forced expression of NRF in A549 cells by an NRF expression plasmid suppressed IL-8/CXCL8 expression. Hence, we describe a novel negative regulatory mechanism of NE-induced NRF, which is restricted to hASM and mediates the suppression of IL-8/CXCL8 expression.
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PMID:Neutrophil elastase represses IL-8/CXCL8 synthesis in human airway smooth muscle cells through induction of NF-kappa B repressing factor. 1954 52

Endotoxin tolerance reprograms cell responses to LPS by repressing expression of proinflammatory cytokines, while not inhibiting production of anti-inflammatory cytokines and antimicrobial effectors. Molecular mechanisms of induction and maintenance of endotoxin tolerance are incompletely understood, particularly with regard to the impact of endotoxin tolerization on signalosome assembly, activation of adaptor-kinase modules, and expression of negative regulators of TLR signaling in human cells. In this study, we examined LPS-mediated activation of MyD88-dependent and Toll-IL-1R-containing adaptor inducing IFN-beta (TRIF)-dependent pathways emanating from TLR4 and expression of negative regulators of TLR signaling in control and endotoxin-tolerant human monocytes. Endotoxin tolerization suppressed LPS-inducible TLR4-TRIF and TRIF-TANK binding kinase (TBK)1 associations, induction of TBK1 kinase activity, activation of IFN regulatory factor (IRF)-3, and expression of RANTES and IFN-beta. Tolerance-mediated dysregulation of the TLR4-TRIF-TBK1 signaling module was accompanied by increased levels of suppressor of IkappaB kinase-epsilon (SIKE) and sterile alpha and Armadillo motif-containing molecule (SARM). LPS-tolerant cells showed increased expression of negative regulators Toll-interacting protein (Tollip), suppressor of cytokine signaling (SOCS)-1, IL-1R-associated kinase-M, and SHIP-1, which correlated with reduced p38 phosphorylation, IkappaB-alpha degradation, and inhibited expression of TNF-alpha, IL-6, and IL-8. To examine functional consequences of increased expression of Tollip in LPS-tolerized cells, we overexpressed Tollip in 293/TLR4/MD-2 transfectants and observed blunted LPS-inducible activation of NF-kappaB and RANTES, while TNF-alpha responses were not affected. These data demonstrate dysregulation of TLR4-triggered MyD88- and TRIF-dependent signaling pathways and increased expression of negative regulators of TLR signaling in endotoxin-tolerant human monocytes.
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PMID:Endotoxin tolerance dysregulates MyD88- and Toll/IL-1R domain-containing adapter inducing IFN-beta-dependent pathways and increases expression of negative regulators of TLR signaling. 1965 1

Rhinovirus (RV), a ssRNA virus of the picornavirus family, is a major cause of the common cold as well as asthma and chronic obstructive pulmonary disease exacerbations. Viral dsRNA produced during replication may be recognized by the host pattern recognition receptors TLR-3, retinoic acid-inducible gene (RIG)-I, and melanoma differentiation-associated gene (MDA)-5. No study has yet identified the receptor required for sensing RV dsRNA. To examine this, BEAS-2B human bronchial epithelial cells were infected with intact RV-1B or replication-deficient UV-irradiated virus, and IFN and IFN-stimulated gene expression was determined by quantitative PCR. The separate requirements of RIG-I, MDA5, and IFN response factor (IRF)-3 were determined using their respective small interfering RNAs (siRNA). The requirement of TLR3 was determined using siRNA against the TLR3 adaptor molecule Toll/IL-1R homologous region-domain-containing adapter-inducing IFN-beta (TRIF). Intact RV-1B, but not UV-irradiated RV, induced IRF3 phosphorylation and dimerization, as well as mRNA expression of IFN-beta, IFN-lambda1, IFN-lambda2/3, IRF7, RIG-I, MDA5, 10-kDa IFN-gamma-inducible protein/CXCL10, IL-8/CXCL8, and GM-CSF. siRNA against IRF3, MDA5, and TRIF, but not RIG-I, decreased RV-1B-induced expression of IFN-beta, IFN-lambda1, IFN-lambda2/3, IRF7, RIG-I, MDA5, and inflammatory protein-10/CXCL10 but had no effect on IL-8/CXCL8 and GM-CSF. siRNAs against MDA5 and TRIF also reduced IRF3 dimerization. Finally, in primary cells, transfection with MDA5 siRNA significantly reduced IFN expression, as it did in BEAS-2B cells. These results suggest that TLR3 and MDA5, but not RIG-I, are required for maximal sensing of RV dsRNA and that TLR3 and MDA5 signal through a common downstream signaling intermediate, IRF3.
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PMID:Role of double-stranded RNA pattern recognition receptors in rhinovirus-induced airway epithelial cell responses. 1989 46

Here we address the role of RIG-I and TLR3 in differential cytokine responses against Simian Virus 5 (SV5) and two distinct cytokine inducing SV5 mutants. IFN-beta and IL-6 secretion was induced by infection with P/V-CPI-, an SV5 mutant with P/V substitutions, and were reduced by either siRNA-mediated knockdown of RIG-I expression or by expression of a dsRNA-binding protein. TLR3 overexpression did not alter cytokine secretion induced by P/V-CPI- or by Le-(U5C, A14G), an SV5 promoter mutant. TLR3 signaling by addition of exogenously added dsRNA was not blocked by WT SV5 or either SV5 mutant. Unexpectedly, TLR3 activation in infected cells led to enhanced IL-8 secretion, which correlated with increased RIG-I expression. Dominant negative RIG-I and TRIF supported a model whereby TLR3 activation upregulates RIG-I expression and in turn hypersensitizes cells to RIG-I-mediated cytokine secretion. Implications for crosstalk between different innate immunity pathways in mounting antiviral responses to paramyxoviruses are discussed.
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PMID:TLR3-dependent upregulation of RIG-I leads to enhanced cytokine production from cells infected with the parainfluenza virus SV5. 1994 50

IFN-stimulated gene 15 (ISG15), an ubiquitin-like protein, is rapidly induced by IFN-alpha/beta, and ISG15 conjugation is associated with the antiviral immune response. Japanese encephalitis virus (JEV), a mosquito-borne neurotropic flavivirus, causes severe central nervous system diseases. We investigated the potential anti-JEV effect of ISG15 over-expression. ISG15 over-expression in human medulloblastoma cells significantly reduced the JEV-induced cytopathic effect and inhibited JEV replication by reducing the viral titers and genomes (p<0.05, Student's t-test); it also increased activation of the interferon stimulatory response element (ISRE)-luciferase cis-acting reporter in JEV-infected cells (p<0.05, Chi-square test). Furthermore, Western blotting revealed that ISG15 over-expression increased phosphorylation of IRF-3 (Ser396), JAK2 (Tyr1007/1008) and STAT1 (Tyr701 and Ser727) in JEV-infected cells (P<0.05, Chi-square test). Confocal imaging indicated that nucleus translocation of transcription factor STAT1 occurred in ISG15-over-expressing cells but not in vector control cells post-JEV infection. ISG15 over-expression activated the expression of STAT1-dependent genes including IRF-3, IFN-beta, IL-8, PKR and OAS before and post-JEV infection (p=0.063, Student's t-test). The results enabled elucidation of the molecular mechanism of ISG15 over-expression against JEV, which will be useful for developing a novel treatment to combat JEV infection.
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PMID:ISG15 over-expression inhibits replication of the Japanese encephalitis virus in human medulloblastoma cells. 2003 88

TLRs trigger innate immunity that recognizes conserved motifs of invading pathogens, resulting in cellular activation and release of inflammatory factors. The influence of TLR activation on resistance to HIV-1 infection has not been investigated in HIV-1 exposed seronegative (ESN) individuals. PBMCs isolated from heterosexually ESN individuals were stimulated with agonists specific for TLR3 (poly I:C), TLR4 (LPS), TLR7 (imiquimod), and TLR7/8 (ssRNA40). We evaluated expression of factors involved in TLR signaling cascades, production of downstream effector immune mediators, and TLR-expression in CD4+ and CD14+ cells. Results were compared with those obtained in healthy controls (HCs). ESN individuals showed: 1) comparable percentages of CD14+/TLR4+ and CD4+/TLR8+ CD14+/TLR8+ cells; 2) higher responsiveness to poly I:C, LPS, imiquimod, and ssRNA40 stimulation, associated with significantly increased production of IL-1beta, IL-6, TNF-alpha, and CCL3; 3) augmented expression of mRNA specific for other targets (CCL2, CSF3, CSF2, IL-1alpha, IL-8, IL-10, IL-12, cyclooxygenase 2) demonstrated by broader TLRs pathway expression analyses; and 4) increased MyD88/MyD88s(short) ratio, mainly following TLR7/8 stimulation. We also compared TLR-agonist-stimulated cytokine/chemokine production in CD14+ PBMCs and observed decreased IFN-beta production in ESN individuals compared with HCs upon TLR7/8-agonist stimulation. These data suggest that TLR stimulation in ESN individuals results in a more robust release of immunologic factors that can influence the induction of stronger adaptive antiviral immune responses and might represent a virus-exposure-induced innate immune protective phenotype against HIV-1.
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PMID:TLR activation pathways in HIV-1-exposed seronegative individuals. 2012 1

Acanthamoeba keratitis (AK) is a painful, vision-threatening infection caused by pathogenic strains of the protozoan, Acanthamoeba. Toll-like receptors (TLRs), which are important components of innate immunity, have an important role in the detection of foreign pathogens and the signaling cascades in host cells. However, no report on the interaction between Acanthamoeba and TLR has been found. In this study we analyzed the role of the TLR and its signaling pathway in human telomerase-immortalized corneal epithelial cells (HUCLs) and stromal fibroblasts (THSFs) challenged by Acanthamoeba. We show that the expressions of TLR4, myeloid differentiation protein 88 (MyD88), nuclear factor (NF)-kappaB, phospho-IkappaB, phospho-extracellular signal-regulated kinases 1/2 (p-Erk1/2) and the inflammatory cytokines interleukin (IL)-8, tumor necrosis factor (TNF)-alpha and interferon (IFN)-beta were significantly increased in Acanthamoeba-treated cells. Pretreatment with anti-TLR antibodies or the specific inhibitors pyrrolidine dithiocarbamate (PDTC) (for the NF-kappaB pathway) and U0126 (for the ERK pathway) was conducted. It was found that anti-TLR4 antibody attenuated the production of cytokines induced by Acanthamoeba infection. PDTC inhibited the production of IL-8 and TNF-alpha whereas U0126 inhibited the synthesis of IFN-beta. Thus, TLR4 is a receptor for Acanthamoeba and exerts an effect through TLR4-MyD88-NF-kappaB and TLR4-ERK1/2 pathways to induce the secretion of cytokines in human corneal cell lines challenged by Acanthamoeba.
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PMID:TLR4: the receptor bridging Acanthamoeba challenge and intracellular inflammatory responses in human corneal cell lines. 2012 14

TLRs are central receptors of the innate immune system that drive host inflammation and adaptive immune responses in response to invading microbes. Among human TLRs, TLR10 is the only family member without a defined agonist or function. Phylogenetic analysis reveals that TLR10 is most related to TLR1 and TLR6, both of which mediate immune responses to a variety of microbial and fungal components in cooperation with TLR2. The generation and analysis of chimeric receptors containing the extracellular recognition domain of TLR10 and the intracellular signaling domain of TLR1, revealed that TLR10 senses triacylated lipopeptides and a wide variety of other microbial-derived agonists shared by TLR1, but not TLR6. TLR10 requires TLR2 for innate immune recognition, and these receptors colocalize in the phagosome and physically interact in an agonist-dependent fashion. Computational modeling and mutational analysis of TLR10 showed preservation of the essential TLR2 dimer interface and lipopeptide-binding channel found in TLR1. Coimmunoprecipitation experiments indicate that, similar to TLR2/1, TLR2/10 complexes recruit the proximal adaptor MyD88 to the activated receptor complex. However, TLR10, alone or in cooperation with TLR2, fails to activate typical TLR-induced signaling, including NF-kappaB-, IL-8-, or IFN-beta-driven reporters. We conclude that human TLR10 cooperates with TLR2 in the sensing of microbes and fungi but possesses a signaling function distinct from that of other TLR2 subfamily members.
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PMID:Human TLRs 10 and 1 share common mechanisms of innate immune sensing but not signaling. 2034 27

Innate immune responses contribute to synovial inflammation in rheumatoid arthritis. The present study was designed to investigate the contribution of IFN regulatory factor (IRF)3 and IRF7 to type I IFN-regulated gene expression in synoviocytes. Fibroblast-like synoviocytes were stimulated with polyinosinic-polycytidylic acid (poly [I-C]) after transfection with IRF3 or IRF7 small interfering RNA to knockdown transcription factor expression. Western blots, luciferase assay after transfection with reporter constructs, quantitative PCR, and AP-1 DNA binding ELISA were performed to evaluate the role of IRF3 and IRF7 in poly (I-C)-induced signaling and synoviocyte gene expression. IRF3 regulates IFN-stimulated response element (ISRE) promoter activity as well as IFN-beta, IRF5, IRF7, RANTES, IFN-inducible protein-10, MCP-1, and MIP1alpha gene expression in response to poly (I-C). IRF7 knockdown modestly decreased a subset of genes and ISRE activity, although the results were not statistically significant. Surprisingly, IRF3 knockdown almost completely blocked expression of additional genes in which the ISRE is not traditionally considered a dominant promoter site in fibroblast-like synoviocytes, including matrix metalloproteinase (MMP)3, MMP9, IL-6, and IL-8. Transcription factor activation studies demonstrated a role for IRF3 in regulation of c-Jun phosphorylation and AP-1 binding. IRF3 rather than IRF7 regulates poly (I-C)-induced type I IFN responses in human synoviocytes by increasing ISRE promoter activity. IRF3 also partially regulates expression of other cytokines and MMP through activation of c-Jun and the AP-1 promoter site. Targeting synoviocyte IRF3 represents a potential approach to suppress diverse mediators while limiting suppression of IRF7-mediated immune responses.
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PMID:Synoviocyte innate immune responses: II. Pivotal role of IFN regulatory factor 3. 2048 55

Endothelial dysfunction is involved in various cardiovascular diseases such as atherosclerosis. Endothelial progenitor cells (EPCs) contribute to re-endothelialization and neo-vascularization, and the increase of EPCs in peripherial circulation benefits the prognosis of cardiovascular disease. However, little is known about the biological stimuli that initiate the proliferation and the maintenance of stem cell phenotype of EPCs. Here we reported that human umbilical vein blood derived EPCs expressed gene transcripts coding for Toll-like receptor (TLR) 1-6, TLR8-10, TLR4 co-receptor CD14, and myeloid differentiation factor 88 (MyD88), a TLR adaptor molecule. Protein expression of TLR2, 4, CD14, and MyD88 was also detected by FACS or Western blot. The activation of TLR4 by LPS modulated the expression of TLRs, induced the phosphorylation of NF-kappaB, P38, and ERK42/44, and up-regulated the gene expression of cytokines IL-8, IFN-alpha, IFN-beta, and TNF-alpha, suggesting EPCs expressed functional TLR4. Unexpectedly LPS treatment failed to induce apoptosis in EPCs, but instead promoted cell proliferation of EPCs. Furthermore, the treatment of EPCs with LPS up-regulated stem cell markers AC133 and CD34 in both mRNA and protein levels, and down-regulated the protein expression of differential marker eNOS. These results suggested that TLR4 functions to maintain the stem cell phenotype of EPCs and enlarge its population, which reveals a novel aspect of the multiple-faced TLR biology, and may open new prospects for using TLR4 agonists to promote the production of EPCs for clinical use.
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PMID:The expression of functional Toll-like receptor 4 is associated with proliferation and maintenance of stem cell phenotype in endothelial progenitor cells (EPCs). 2050 7


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