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)

Two types of synthetic peptidoglycan fragments, diaminopimelic acid (DAP)-containing desmuramylpeptides (DMP) and muramyldipeptide (MDP), induced secretion of interleukin (IL)-8 in a dose-dependent manner in human monocytic THP-1 cells, although high concentrations of compounds are required as compared with chemically synthesized Toll-like receptor (TLR) agonists mimicking bacterial components: TLR2 agonistic lipopeptide (Pam3CSSNA), TLR4 agonistic lipid A (LA-15-PP) and TLR9 agonistic bacterial CpG DNA. We found marked synergistic IL-8 secretion induced by MDP or DAP-containing DMP in combination with synthetic TLR agonists in THP-1 cells. Suppression of the mRNA expression of nucleotide-binding oligomerization domain (NOD)1 and NOD2 by RNA interference specifically inhibited the synergistic IL-8 secretion induced by DMP and MDP with these TLR agonists respectively. In accordance with the above results, enhanced IL-8 mRNA expression and the activation of nuclear factor (NF)-kappaB induced by MDP or DMP in combination with synthetic TLR agonists were markedly suppressed in NOD2- and NOD1-silenced cells respectively. These findings indicated that NOD2 and NOD1 are specifically responsible for the synergistic effects of MDP and DMP with TLR agonists, and suggested that in host innate immune responses to invading bacteria, combinatory dual signalling through extracellular TLRs and intracellular NODs might lead to the synergistic activation of host cells.
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PMID:Muramyldipeptide and diaminopimelic acid-containing desmuramylpeptides in combination with chemically synthesized Toll-like receptor agonists synergistically induced production of interleukin-8 in a NOD2- and NOD1-dependent manner, respectively, in human monocytic cells in culture. 1561 23

Both NOD2/CARD15 alleles are mutated in approximately 10% of Crohn's disease patients, causing loss of functional responses to low-dose muropeptide agonists. We hypothesized that NOD2 mutations may also impair NOD1/CARD4 responses, supported by data suggesting NOD2 1007fs/1007fs patients had reduced responses to a putative NOD1 agonist, diaminopimelic acid-containing muramyl tripeptide (M-TriDAP). We measured peripheral blood mononuclear cell (n = 8 NOD2 wild type, n = 4 1007fs/1007fs, n = 6 702Trp/1007fs, n = 5 702Trp/702Trp, n = 3 908Arg/1007fs) responses to NOD1 agonists alone (IL-8/TNF-alpha), and agonist enhancement of lipopolysaccharide (LPS) responses (IL-1beta). Significant responses were seen with M-TriDAP at 10 nM (as with NOD2 agonists), but only at > or =100 nM with FK565/TriDAP. M-TriDAP induced IL-8/TNF-alpha secretion, and enhancement of LPS IL-1beta responses was significantly reduced between NOD2 double mutation carriers versus healthy controls, whereas there was no difference with FK565 or TriDAP stimulation, or between 1007fs/1007fs cells and other genotypes. M-TriDAP contains both NOD1 (gamma-D-Glu-mesoDAP) and NOD2 (MurNAc-L-Ala-D-Glu) minimal structures whereas FK565/TriDAP contain only NOD1 activating structures. M-TriDAP has dual NOD1/NOD2 agonist activity in primary cells, possibly due to different intracellular peptidoglycan processing compared to the HEK293 cell system typically used for agonist specificity studies. Responses to specific NOD1 agonists are unaffected by NOD2 genotype, suggesting independent action of the NOD1 and NOD2 pathways.
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PMID:Normal responses to specific NOD1-activating peptidoglycan agonists in the presence of the NOD2 frameshift and other mutations in Crohn's disease. 1701 77

Moraxella catarrhalis is an important pathogen in patients with chronic obstructive lung disease (COPD). While M. catarrhalis has been categorized as an extracellular bacterium so far, the potential to invade human respiratory epithelium has not yet been explored. Our results obtained by electron and confocal microscopy demonstrated a considerable potential of M. catarrhalis to invade bronchial epithelial (BEAS-2B) cells, type II pneumocytes (A549) and primary small airway epithelial cells (SAEC). Moraxella invasion was dependent on cellular microfilament as well as on bacterial viability, and characterized by macropinocytosis leading to the formation of lamellipodia and engulfment of the invading organism into macropinosomes, thus indicating a trigger-like uptake mechanism. In addition, the cells examined expressed TLR2 as well as NOD1, a recently found cytosolic protein implicated in the intracellular recognition of bacterial cell wall components. Importantly, inhibition of TLR2 or NOD1 expression by RNAi significantly reduced the M. catarrhalis-induced IL-8 secretion. The role of TLR2 and NOD1 was further confirmed by overexpression assays in HEK293 cells. Overall, M. catarrhalis may employ lung epithelial cell invasion to colonize and to infect the respiratory tract, nonetheless, the bacteria are recognized by cell surface TLR2 and the intracellular surveillance molecule NOD1.
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PMID:Moraxella catarrhalis is internalized in respiratory epithelial cells by a trigger-like mechanism and initiates a TLR2- and partly NOD1-dependent inflammatory immune response. 1705 39

Toll-like receptors (TLRs) recognize common motifs, pathogen-associated molecular patterns (PAMPs), in microorganisms. Bacterial PAMPs are mainly distributed on cell-surfaces. Peptidoglycans (PGNs) are ubiquitous constituents of bacterial cell walls. Muramyldipeptide (MDP; N-acetylmuramyl-l-alanyl-d-isoglutamine) is a common and key structure of PGNs and exhibits most the of bioactivities of PGNs. Recently, the intracellular receptor for MDP was revealed to be NOD2. Another bioactive moiety of PGNs, diaminopimelic acid (DAP) containing desmuramylpeptides (DMPs), senses another intracellular receptor, NOD1. MDP-primed mice exhibited hyper-responses to endotoxin and other bacterial components, which sense Toll-like receptors (TLRs), although MDP itself does not exhibit apparent activity in mice. On the other hand, DMPs exhibited definite activity in mice, and the most powerful DMP, FK565, exhibited stronger priming activity than MDP. In human monocytic cells, both MDP and DMPs exhibited definite activities; marked synergistic interleukin (IL)-8 secretion was induced by DMPs and MDP in combination with synthetic TLR agonists, and suppression of the mRNA expressions of NOD1 and NOD2, respectively, by RNA interference specifically inhibited synergistic IL-8 secretion. In human dendritic cells (DCs), synergistic T helper type 1 responses are induced by combined stimulations of synthetic NOD and TLR agonists. Considering these findings altogether, in host-bacteria interactions, host cells should recognize bacteria via both TLRs and NODs, which might induce synergistic innate and adaptive immune responses.
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PMID:Enhancement of TLR-mediated innate immune responses by peptidoglycans through NOD signaling. 1710 Jun 19

Since human gingival fibroblasts are the major cells in periodontal tissues, we hypothesized that gingival fibroblasts are endowed with receptors for bacterial components, which induce innate immune responses against invading bacteria. We found clear mRNA expression of Toll-like receptors (TLR)1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, MD-2, MyD88, NOD1, and NOD2 in gingival fibroblasts. Gingival fibroblasts constitutively expressed these molecules. Upon stimulation with chemically synthesized ligands mimicking microbial products for these receptors, the production of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1, was markedly up-regulated. Furthermore, the production of pro-inflammatory cytokines induced by TLR and NOD ligands was significantly inhibited by an RNA interference assay targeted to NF-kappaB. These findings indicate that these innate immunity-related molecules in gingival fibroblasts are functional receptors involved in inflammatory reactions in periodontal tissues, which might be responsible for periodontal pathogenesis.
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PMID:Functional TLRs and NODs in human gingival fibroblasts. 1731 57

Anti-neutrophil cytoplasmic Abs against proteinase 3 (PR3) have been detected in relation to a wide range of inflammatory conditions, and the interaction of anti-PR3 Abs with leukocytes provokes cell activation, although how is not clear. Flow cytometric analysis revealed an increase in cell-surface CD14, Toll-like receptor (TLR)2, TLR4 and intracellular TLR3, TLR7, TLR8, TLR9, NOD1 and NOD2 expression during anti-PR3 priming in human monocytic THP-1 cells. Anti-RP3 Abs markedly promoted the release of IL-8 induced by chemically synthesized TLR and NOD ligands mimicking bacterial components: TLR2-agonistic lipopeptide (FSL-1), TLR3-agonistic poly I:C, TLR4-agonistic lipid A (LA-15-PP), TLR7/8-agonistic single stranded RNA (ssPolyU), TLR9-agonistic bacterial CpG DNA, NOD1-agonistic FK156/565 and NOD2-agonistic muramyldipeptide (MDP) in THP-1 cells and human peripheral blood mononuclear cells, although sole incubation with anti-PR3 Abs induced only a low level of IL-8. The priming response was evident after 2h of preincubation with anti-PR3 Abs and peaked after 6h. Priming was also observed for the production of TNF-alpha and monocyte chemoattractant protein-1. An RNA interference assay revealed that anti-PR3 Abs activated THP-1 cells in a PR3- and protease-activated receptor-2-dependent manner. Furthermore, the anti-PR3 Ab-mediated cell activation was significantly abolished by RNA interference targeted at PR3 mRNA and by inhibition of phospholipase C and NF-kappaB. These results suggest that anti-PR3 Abs prime human monocytic cells to produce cytokines upon stimulation with various bacterial components by up-regulating the TLR and NOD signaling pathway, and that these mechanisms may actively participate in the inflammatory process.
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PMID:Antibodies to proteinase 3 prime human monocytic cells via protease-activated receptor-2 and NF-kappaB for Toll-like receptor- and NOD-dependent activation. 1745 51

Genetic factors, Helicobacter pylori infection, salt over-uptake, decreased vegetable/fruit consumption, smoking, and metabolic syndrome are risk factors of human gastric cancer. Germline mutations of CDH1 gene, and SNPs of PTPN11 (SHP2), TLR4, IL1B, TNFA, BMP6, GDF15 and RUNX3 genes are associated with gastric cancer. Helicobacter pylori activates CagA-SHP2-ERK and peptidoglycan-NOD1-NFkappaB signaling cascades in gastric epithelial cells using type IV secretion system, and also TRAF6-MAP3K7-NFkappaB and TRAF6-MAP3K7-AP-1 signaling cascades in epithelial and immune cells through lipopolysaccharide recognition by TLR2 or TLR4. IL-1beta, IL-6, IL-8, TNFalpha and IFNgamma are elevated in gastric mucosa with Helicobacter pylori infection. IL-6 and TNFalpha induce upregulation of WNT5A and WNT10B, respectively. WNT signals are transduced to beta-catenin-TCF/LEF, RhoA, JNK, PKC, NFAT, and NLK signaling cascades. WNT-beta-catenin-TCF/LEF signaling induces upregulation of MYC, CCND1, WISP1, FGF20, JAG1 and DKK1 genes. Notch signals are transduced to CSL-NICD-MAML and NFkappaB signaling cascades. FGF signals are transduced to ERK, PI3K-AKT, PKC, and NFAT signaling cascades. Helicobacter pylori infection induces SHH upregulation in parietal cell lineage, while BMP signals induce IHH upregulation in pit cell lineage. Hedgehog signals induce upregulation of GLI1, PTCH1, CCND2, FOXL1, JAG2 and SFRP1 genes. JAG1 and JAG2 activate Notch signaling, while DKK1 and SFRP1 inhibit WNT signaling. Stem cell signaling network, consisting of WNT, Notch, FGF, Hedgehog and BMP signaling pathways, is activated during chronic Helicobacter pylori infection. Epigenetic silencing of SFRP1 gene occurs in the earlier stage of carcinogenesis in the stomach, while amplification and overexpression of FGFR2 gene in the later stage. Dysregulation of the stem cell signaling network due to the accumulation of germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration gives rise to gastric cancer. SNP typing and custom-made microarray analyses on genes encoding stem cell signaling molecules could be utilized for the personalized medicine.
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PMID:Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. 1756 83

Gingipains (HRgpA, RgpB and Kgp) are cysteine proteinases and virulence factors of Porphyromonas gingivalis, the major causative bacterium of periodontal disease. To study synergistic effects of gingipains and signalling via Toll-like receptors (TLRs) and NOD1/2, we investigated effects of a gingipain on the secretion of proinflammatory cytokines from monocytic THP-1 cells in the presence of pathogen-associated molecular patterns (PAMPs). Gingipains stimulated interleukin (IL)-8's secretion from THP-1 cells, which was completely inhibited by proteinase inhibitors of gingipain and increased in the presence of PAMPs. Synergistic effects of gingipains and PAMPs were also seen in the secretion of IL-6 and MCP-1 and reduced to about 50% the secretion of IL-8 from THP-1 cells treated with siRNA targeting either protease-activated receptor (PAR)-1, -2 or -3. PAR agonist peptides mimicked the synergistic effects of gingipains with PAMPs. These results indicate that gingipains stimulate the secretion of cytokines from monocytic cells through the activation of PARs with synergistic effects by PAMPs. This is the first report of synergism of signalling via PARs, and TLRs or NOD1/2. The host defence system against P. gingivalis may be triggered through the activation of PARs by gingipains and augmented by PAMPs from this pathogen via TLRs or NOD1/2.
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PMID:Gingipains from Porphyromonas gingivalis synergistically induce the production of proinflammatory cytokines through protease-activated receptors with Toll-like receptor and NOD1/2 ligands in human monocytic cells. 1818 86

Microbial detection requires the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) that are distributed on the cell surface and within the cytosol. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family functions as an intracellular PRR that triggers the innate immune response. The mechanism by which PAMPs enter the cytosol to interact with NLRs, particularly muropeptides derived from the bacterial proteoglycan cell wall, is poorly understood. PEPT2 is a proton-dependent transporter that mediates the active translocation of di- and tripeptides across epithelial tissues, including the lung. Using computational tools, we initially established that bacterial dipeptides, particularly gamma-D-glutamyl-meso-diaminopimelic acid (gamma-iE-DAP), are suitable substrates for PEPT2. We then determined in primary cultures of human upper airway epithelia and transiently transfected CHO-PEPT2 cell lines that gamma-iE-DAP uptake was mediated by PEPT2 with an affinity constant of approximately 193 microM, whereas muramyl dipeptide was not transported. Exposure to gamma-iE-DAP at the apical surface of differentiated, polarized cultures resulted in activation of the innate immune response in an NOD1- and RIP2-dependent manner, resulting in release of IL-6 and IL-8. Based on these findings we report that PEPT2 plays a vital role in microbial recognition by NLR proteins, particularly with regard to airborne pathogens, thereby participating in host defense in the lung.
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PMID:Bacterial peptide recognition and immune activation facilitated by human peptide transporter PEPT2. 1847 68

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


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