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

PTM (post-translational modification) is the chemical modification of a protein after its translation. The well-studied PTM is phosphorylation, but, recently, PTMs have been re-focused by extensive studies on histone modifications and the discovery of the ubiquitin system. Histone acetylation is the well-established epigenetic regulator for gene expression. Recent studies show that different patterns of PTMs and cross-talk of individual modifications (acetylation, methylation, phosphorylation) are keys of gene regulation (known as the 'histone code'). As well as histone, non-histone proteins are also targets of acetylation. For instance, NF-kappaB (nuclear factor kappaB), a transcriptional factor, is regulated dynamically by acetylation/deacetylation. Acetylation of NF-kappaB [RelA (p65)] at Lys(310) enhances its transcriptional activity, which is inhibited by SIRT1 deacetylase, type III HDAC (histone deacetylase). We also found that acetylated NF-kappaB preferentially bound to the IL-8 (interleukin 8) gene promoter, but not to GM-CSF (granulocyte/macrophage colony-stimulating factor), suggesting NF-kappaB acetylation is involved in selective gene induction as well as an increased level of transcription. A receptor of glucocorticoid, a potent anti-inflammatory agent, is also a target of acetylation. The glucocorticoid receptor is highly acetylated after ligand binding but its deacetylation is necessary for gene repression through binding to NF-kappaB. As well as acetylation, other PTMs, such as nitration, carbonylation and ubiquitination on transcriptional/nuclear factors, are taking part in the inflammatory process. Cross-talk of individual modifications on proteins deserves further evaluation in the future (as 'protein code').
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PMID:Impact of post-translational modifications of proteins on the inflammatory process. 1737 Dec 60

We identify matrix metalloproteinase (MMP)-8, the polymorphonuclear (PMN) leukocyte collagenase, as a critical mediator initiating lipopolysaccharide (LPS)-responsiveness in vivo. PMN infiltration towards LPS is abrogated in Mmp8-null mice. MMP-8 cleaves LPS-induced CXC chemokine (LIX) at Ser(4)-Val(5) and Lys(79)-Arg(80). LIX bioactivity is increased upon N-terminal cleavage, enhancing intracellular calcium mobilization and chemotaxis upon binding its cognate receptor, CXCR2. As there is no difference in PMN chemotaxis in Mmp8-null mice compared with wild-type mice towards synthetic analogues of MMP-8-cleaved LIX, MMP-8 is not essential for extravasation or cell migration in collagenous matrices in vivo. However, with biochemical redundancy between MMPs 1, 2, 9, and 13, which also cleave LIX at position 4 approximately 5, it was surprising to observe such a markedly reduced PMN infiltration towards LPS and LIX in Mmp8-/- mice. This lack of physiological redundancy in vivo identifies MMP-8 as a key mediator in the regulation of innate immunity. Comparable results were found with CXCL8/IL-8 and CXCL5/ENA-78, the human orthologues of LIX. MMP-8 cleaves CXCL8 at Arg(5)-Ser(6) and at Val(7)-Leu(8) in CXCL5 to activate respective chemokines. Hence, rather than collagen, these PMN chemoattractants are important MMP-8 substrates in vivo; PMN-derived MMP-8 cleaves and activates LIX to execute an in cis PMN-controlled feed-forward mechanism to orchestrate the initial inflammatory response and promote LPS responsiveness in tissue.
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PMID:LPS responsiveness and neutrophil chemotaxis in vivo require PMN MMP-8 activity. 1737 98

The protective effects of amino acids against H 2O 2-induced oxidative stress were investigated in an in vitro assay using human intestinal epithelial cells. Caco-2 cells were pretreated with amino acids (1, 2, and 5 mM) for 2 h and then stimulated with 1 mM H 2O 2 for 6 h. The secretion of IL-8, a proinflammatory mediator, was determined by ELISA as an indicator of tissue oxidative stress. The inhibition of H 2O 2-induced IL-8 secretion from Caco-2 cells was observed by pretreatment with Cys, Val, Ile, Leu, Trp, His, Lys, and Ala. Cys enhanced glutathione (GSH) biosynthesis enzyme activity and increased cellular GSH levels. Branched-chain amino acids such as Val, Ile, and Leu elevated activities of GSH S-transferase (GST) and catalase. Trp, His, and Lys caused increases in GST activity. Ala enhanced GSH reductase activity. These data suggest that specific amino acids exert protective effects against tissue oxidative stress in intestinal epithelial cells based on the structure.
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PMID:Antioxidative activity of amino acids on tissue oxidative stress in human intestinal epithelial cell model. 1788 54

1. Human endothelial cells express proteinase-activated receptor-2 (PAR-2), inflammatory cytokines and trypsin (EC 3.4.21.4). However, little is known about the mechanism through which trypsin induces cytokine release from endothelial cells. 2. In the present study, we investigated the effect of trypsin on cytokine release from primary cultures of human umbilical vein endothelial cells (HUVEC) using an antibody based protein microarray and ELISA. 3. The results showed that 1 microg/mL trypsin induced release of 32 different inflammatory factors, whereas 100 micromol/L Ser-Leu-Ile-Gly-Lys-Val-NH2 (SLIGKV-NH2) only stimulated secretion of 16 inflammatory factors from HUVEC, as assessed by an antibody based protein microarray. Because the release of interleukin (IL)-1a, IL-8, IL-10 and IL-12 was markedly increased following PAR-2 activation, their release was investigated further using ELISA. Increases in release of up to approximately 4.8-, 4.3-, 4.1- and 1.8-fold were observed for IL-1a, IL-10, IL-12 and IL-8, respectively, when HUVEC were challenged with trypsin for 16 h. Agonist peptides of PAR-2, namely SLIGKV-NH2 and trans-cinnamoyl-Leu-Ile-Gly-Arg-Leu-Orn-NH2 (tc-LIGRLO-NH2), also provoked significant release of IL-8. Trypsin-induced cytokine release was inhibited by its inhibitors soybean trypsin inhibitor, alpha1-antitrypsin and the inhibitor peptide of PAR-2 Phe-Ser-Leu-Leu-Arg-Tyr-NH2 (FSLLRY-NH2). 4. These data indicate the action of trypsin on HUVEC is most likely through activation of PAR-2, suggesting that PAR-2-related mechanisms are involved in the inflammatory process in humans.
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PMID:Induction of inflammatory cytokine release from human umbilical vein endothelial cells by agonists of proteinase-activated receptor-2. 1804 34

Cysteine proteinases from Porphyromonas gingivalis, or gingipains, are considered to be key virulence factors of the bacterium in relation to periodontal diseases. Incubation of human oral epithelial cells with lysine-specific gingipain (Kgp) and high-molecular-mass arginine-specific gingipain (HRgpA) resulted in a decrease in the production of interleukin (IL)-8, but not in the production of other pro-inflammatory cytokines. In contrast, arginine-specific gingipain 2 (RgpB) increased IL-8 production. RNA interference assays demonstrated that Kgp- and HRgpA-mediated downregulation and RgpB-mediated upregulation occurred through protease-activated receptor (PAR)-1 and PAR-2 signalling. Although the RgpB-mediated upregulation of IL-8 production occurred through nuclear factor-kappa B (NF-kappaB), the Kgp- and HRgpA-mediated downregulation was not negated in NF-kappaB-silenced cells. Both the haemagglutinin and the enzymic domains are required for Kgp and HRgpA to downregulate the production of IL-8 in human oral epithelial cells, and the two domains are thought to co-exist. These results suggest that gingipains preferentially suppress IL-8, resulting in attenuation of the cellular recognition of bacteria, and as a consequence, sustain chronic inflammation.
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PMID:Dual regulation of interleukin-8 production in human oral epithelial cells upon stimulation with gingipains from Porphyromonas gingivalis. 1834 72

Rosette nanotubes (RNT) are a new class of metal-free organic nanotubes synthesized through self-assembly. Because of the wide range of potential biomedical applications associated with these materials, it is necessary to evaluate their potential in vitro toxicity. Here the cytotoxicity of a lysine-functionalized nanotube (RNT-K) in a human Calu-3 pulmonary epithelial cell line is investigated. The cells were treated with media only (control), lysine (50 mg mL(-1)), RNT-K (1, 5, and 50 microg mL(-1)), Min-U-Sil quartz microparticles (QM; 80 microg mL(-1)), and lipopolysaccharide (LPS; 1 microg mL(-1)). The supernatants were analyzed at 1, 6, and 24 h after treatment for the expression of three proinflammatory mediators: IL-8, TNF-alpha and EMAP-II. Cellular viability determined with the Trypan blue assay is significantly reduced in the QM and high-dose RNT-treated groups. TNF-alpha and EMAP-II are undetectable by enzyme-linked-immunosorbent assay (ELISA) in the supernatant of all groups. Although IL-8 concentrations do not differ between treatments, its concentrations increase with time within each of the groups. Quantitative reverse-transcriptase polymerase chain reaction (qRTPCR) of IL-8 mRNA shows increased expression in the high-dose RNT-treated groups at both 1 and 6 h, while an adhesion molecule, ICAM-1 mRNA, shows the greatest increase at 6 h in the QM-treated group. In summary, RNT-K neither reduces cell viability at moderate doses nor does it induce a time-dependent inflammatory response in pulmonary epithelial cells in vitro.
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PMID:Low inflammatory activation by self-assembling Rosette nanotubes in human Calu-3 pulmonary epithelial cells. 1853 89

Legionella pneumophila causes severe pneumonia. Acetylation of histones is thought to be an important regulator of gene transcription, but its impact on L. pneumophila-induced expression of proinflammatory cytokines is unknown. L. pneumophila strain 130b induced the expression of the important chemoattractant IL-8 and genome-wide histone modifications in human lung epithelial A549 cells. We analyzed the IL-8-promoter and found that histone H4 was acetylated and H3 was phosphorylated at Ser(10) and acetylated at Lys(14), followed by transcription factor NF-kappaB. Recruitment of RNA polymerase II to the IL-8 promoter corresponded with increases in gene transcription. Histone modification and IL-8 release were dependent on p38 kinase and NF-kappaB pathways. Legionella-induced IL-8 expression was decreased by histone acetylase (HAT) inhibitor anacardic acid and enhanced by histone deacetylase (HDAC) inhibitor trichostatin A. After Legionella infection, HATs p300 and CREB-binding protein were time-dependently recruited to the IL-8 promoter, whereas HDAC1 and HDAC5 first decreased and later reappeared at the promoter. Legionella specifically induced expression of HDAC5 but not of other HDACs in lung epithelial cells, but knockdown of HDAC1 or 5 did not alter IL-8 release. Furthermore, Legionella-induced cytokine release, promoter-specific histone modifications, and RNA polymerase II recruitment were reduced in infection with flagellin-deletion mutants. Legionella-induced histone modification as well as HAT-/HDAC-dependent IL-8 release could also be shown in primary lung epithelial cells. In summary, histone acetylation seems to be important for the regulation of proinflammatory gene expression in L. pneumophila infected lung epithelial cells. These pathways may contribute to the host response in Legionnaires' disease.
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PMID:Histone acetylation and flagellin are essential for Legionella pneumophila-induced cytokine expression. 1860 45

Previous studies demonstrated that ING4 as a novel member of ING (inhibitor of growth) family has potential effect on tumor inhibition via multiple pathways. However, adenovirus-mediated ING4 expression in inhibition of human tumors has not been reported. To explore its therapeutic effect on human lung carcinoma, we constructed a recombinant adenoviral vector Ad-ING4 expressing the humanized ING4 gene derived from murine ING4 with two amino acid modifications at residue 66 (Arg to Lys) and 156 (Ala to Thr) by site-directed mutagenesis. We demonstrated that Ad-ING4-mediated transfection of A549 human lung carcinoma cells induced cell apoptosis, altered cell cycle with S phase reduction and G2/M phase arrest, suppressed cell invasiveness, and down-regulated IL-6, IL-8, MMP-2, and MMP-9 expression of transfected tumor cells. In athymic mice bearing A549 lung tumors, intratumoral injections of Ad-ING4 suppressed the tumor growth and reduced the tumor microvessel formation. Therefore, Ad-ING4 may be useful in gene therapy of human lung carcinoma.
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PMID:Adenovirus-mediated ING4 expression suppresses lung carcinoma cell growth via induction of cell cycle alteration and apoptosis and inhibition of tumor invasion and angiogenesis. 1878 75

Recent studies have demonstrated that ING4, as a novel member of the ING (inhibitor of growth) family, has a potential effect on tumor inhibition via multiple pathways. However, adenovirus-mediated ING4 expression in the application of gene therapy for pancreatic carcinoma has not been reported. To explore its therapeutic effect on human pancreatic carcinoma, we constructed a recombinant adenoviral vector, Ad-ING4, expressing the green fluorescent protein (GFP) marker gene and the tumor-suppressor gene, humanized ING4 derived from murine ING4 with two amino-acid modifications at residues 66 (Arg to Lys) and 156 (Ala to Thr) by site-directed mutagenesis. We demonstrated that Ad-ING4-mediated transfection of PANC-1 human pancreatic carcinoma cells inhibited cell growth, altered the cell cycle with S-phase reduction and G2/M phase arrest, induced apoptosis, and downregulated interleukin (IL)-6 and IL-8 expression of transfected tumor cells. In athymic mice bearing the PANC-1 human pancreatic tumors, intratumoral injections of Ad-ING4 suppressed the tumor growth, downregulated CD34 expression, and reduced the tumor microvessel formation. Therefore, this study will provide a framework for future clinical application of Ad-ING4 in human pancreatic carcinoma gene therapy.
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PMID:Adenovirus-mediated ING4 expression suppresses pancreatic carcinoma cell growth via induction of cell-cycle alteration, apoptosis, and inhibition of tumor angiogenesis. 1940 49

Dendritic cell (DC) maturation in response to contact sensitizers is a crucial step in the induction of sensitization reactions; however the underlying mechanism of activation remains unknown. To test whether the extent of protein haptenation is a determinant in DC maturation, we tested the effect of five dinitrophenyl (DNP) analogues of different reactivity, on maturation markers in the cell line, THP-1. The potencies of the test compounds in upregulating CD54 levels, inducing IL-8 release and triggering p38 MAPK phosphorylation did not correlate with their ability to deplete intracellular glutathione (GSH) levels or cause cell toxicity. However, the compounds' potency at inducing p38 phosphorylation was significantly associated with the amount of intracellular protein adducts formed (p<0.05). Inhibition experiments show that, at least for DNFB, p38 MAP kinase signalling controls compound-specific changes in CD54 expression and IL-8 release. 2D-PAGE analysis revealed that all the DNP analogues appeared to bind similar proteins. The analogues failed to activate NFkB, however, they activated Nrf2, which was used as a marker of oxidative stress. Neither GSH depletion, by use of buthionine sulfoximine, nor treatment with the strongly lysine-reactive hapten penicillin elicited maturation. We conclude that protein haptenation, probably through reactive cysteine residues may be a trigger for maturation events in this in vitro model and that p38 activation may be a discriminatory marker for the classification of potency of chemical sensitizers.
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PMID:Role of protein haptenation in triggering maturation events in the dendritic cell surrogate cell line THP-1. 1942 79


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