Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progressive immunodeficiency in HIV infection is paralleled by a decrease in IL-12 production, a cytokine crucial for cellular immune function. Here we examine the molecular mechanisms by which HIV infection suppresses IL-12 p40 expression. HIV infection of THP-1 myeloid cells resulted in decreased LPS-induced nuclear factor binding to the NF-kappaB, AP-1, and Sp1 sites of the IL-12 p40 promoter. By site-directed mutagenesis we determined that each of these sites was necessary for transcriptional activation of the IL-12 p40 promoter. Binding of NF-kappaB p50, c-Rel, p65, Sp1, Sp3, c-Fos, and c-Jun proteins to their cognate nuclear factor binding sites was somewhat impaired by HV infection, although a role for other as yet unidentified factors cannot be dismissed. The cellular levels of these transcription factors were unaffected by HIV infection, with the exception of a decrease in expression of NF-kappaB p65, consistent with the observed decrease in its binding to the IL-12 p40 promoter following HIV infection. Analysis of regulation of upstream LPS-induced MAP kinases demonstrated impaired phosphorylation of JNK and p38 MAPK, and suppressed phosphorylation and degradation of IkappaBalpha following HIV infection. These results suggest that alterations in nuclear factor binding to numerous sites in the IL-12 p40 promoter, together may contribute to the suppression in IL-12 p40 transcription previously reported. These effects on nuclear factor binding may be a direct effect of HIV infection on the IL-12 p40 promoter, or may occur indirectly as a consequence of altered MAP kinase activation.
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PMID:Disruption of MAP kinase activation and nuclear factor binding to the IL-12 p40 promoter in HIV-infected myeloid cells. 1527 Aug 50

Proteasome inhibition has become a target for antitumour and anti-inflammatory therapy. The present study investigated the influence of cysteine proteinase and proteasome inhibitors on chemokine production in lung epithelial cells and monocytic cells. The lung carcinoma cell lines A549, SK-MES, NCI-H727, virus-transformed bronchial epithelial cell line BEAS-2B, primary lung epithelial cells, and the acute monocytic leukaemia cell lines Mono-Mac-6 and THP-1 were incubated with proteasome (N-acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN), beta-lactone) or cysteine proteinase inhibitor (L-trans-Epoxysuccinyl-Leu-3-methylbutylamide-ethyl ester) and the influence on chemokine production (interleukin-8: IL-8, monocyte chemoattractant protein-1, RANTES) was quantified at protein and mRNA levels. Inhibition of proteasome activity by ALLN and beta-lactone resulted in significantly increased IL-8 secretion (5- to 22-fold). Cysteine proteinase inhibitors did not influence chemokine production. The simultaneous rise in IL-8 mRNA was caused by an increased half-life of mRNA and increased RNA synthesis. Moreover, analysis of transcription factor activation revealed induction of activator protein-1 (c-Jun) activity by proteasome inhibition, whereas nuclear factor-kappaB (p50 and p65) was not activated. The significant increase in IL-8 production after proteasome inhibition was also observed in primary lung epithelial cells and in monocytic cells. In addition, the secreted IL-8 was biologically active as shown by the neutrophil chemotaxis assay. In conclusion, it was shown that proteasome inhibitors stimulate interleukin-8 secretion in lung epithelial cells and monocytic cells, thus recruiting neutrophils.
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PMID:Proteasome inhibitors modulate chemokine production in lung epithelial and monocytic cells. 1529 3

Paraoxonase 2 (PON2) is a member of the paraoxonases gene family. PON2 is ubiquitously present in cells, including macrophages, and it was shown to protect against cellular oxidative stress. The aim of the present study was to analyze mechanisms involved in PON2 expression during monocyte/macrophage differentiation. PON2 expression was analyzed in vitro in THP-1 cells differentiated with 1alpha,25-dihydroxyvitamin D3 and in vivo in mouse peritoneal macrophages (MPM) isolated at increasing time intervals after intraperitoneal thioglycollate injection. PON2 expression (mRNA and protein) and activity gradually increased during monocyte/macrophage differentiation, up to five fold and eight fold in vitro and in vivo, respectively. This effect was associated with a gradual increase in cellular superoxide anion production. Supplementation of vitamin E to Balb/C mice inhibited the reduced nicotinamide adenine dinuleotide phosphate (NADPH)-oxidase-dependent increase in cellular superoxide anion production by 50% and down-regulated PON2 mRNA expression and activity by 30 and 60%, respectively. Furthermore, PON2 expression was lower by nine fold in MPM isolated from P47(phox-/-) (inactive NADPH oxidase) mice, in comparison to MPM from control mice. PON2 expression was found to be regulated, at least in part, by the transcription factor AP-1, as suggested by decreased JDP2 (AP-1 repressor) protein expression in the nucleus and by decreased PON2 expression in the presence of a Jun N-terminal kinase inhibitor (SP600125). The present study demonstrates, for the first time, that PON2 expression increases in monocytes during their maturation into macrophage as a result of NADPH-oxidase activation, and this process is partly regulated by the transcription factor AP-1. PON2 stimulation may represent a compensatory mechanism against the increase in cellular superoxide anion production and atherogenesis.
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PMID:Paraoxonase 2 (PON2) expression is upregulated via a reduced-nicotinamide-adenine-dinucleotide-phosphate (NADPH)-oxidase-dependent mechanism during monocytes differentiation into macrophages. 1554 23

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic proinflammatory cytokine that modulates a broad range of inflammatory and immunological processes. We have investigated the potential immunomodulatory properties of prostaglandin E2 (PGE2) by examining the molecular mechanism by which the eicosanoid suppresses T-cell-derived interleukin-17 (IL-17)-induced TNF-alpha mRNA expression and protein synthesis in human macrophages and rheumatoid arthritis-affected synovial fibroblasts. Initial studies confirmed that PGE2 induces egr-1 mRNA expression and protein synthesis by restricted SAPK2/p38 MAPK-dependent activating transcription factor-2 (ATF-2) dimer transactivation of the egr-1 promoter as judged by studies using wild-type (WT) and deletion mutant egr-1 promoter constructs, Northern and Western blotting, and standard and supershift electrophoretic mobility shift analyses. Using human leukemic monocytic THP-1 cells stably transfected with WT and dominant-negative mutant expression constructs of Egr-1, cotransfected or not with a WT pTNF-615SVOCAT construct, we observed that PGE2 inhibition of IL-17-stimulated TNF-alpha mRNA expression and promoter activity was dependent on Egr-1 expression, as mutants of Egr-1, alone or in combination, markedly abrogated any inhibitory effect of PGE2. Standard and supershift electrophoretic mobility shift analysis, signaling "decoy" overexpression studies, and pTNF-615SVOCAT promoter assays using WT and mutant promoter constructs revealed that IL-17-up-regulated promoter activity was largely dependent on ATF-2/c-Jun transactivation. PGE2 suppression of IL-17-induced ATF-2/c-Jun transactivation and DNA binding was dependent on Egr-1-mediated inhibition of induced c-Jun expression. We suggest that egr-1 is an immediate-early PGE2 target gene that may be a key regulatory factor in mediating eicosanoid control of genes involved in the immune and inflammatory responses.
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PMID:Early growth response factor-1 mediates prostaglandin E2-dependent transcriptional suppression of cytokine-induced tumor necrosis factor-alpha gene expression in human macrophages and rheumatoid arthritis-affected synovial fibroblasts. 1564 Jan 48

Activator protein-1 (AP-1) is a transcription factor that plays an important role in regulating the expression of proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha). Many studies have shown that fish oil supplementation inhibits TNF-alpha production in mice and humans; however, the mechanisms remain unclear. In this study, the effects of eicosapentaenoic acid (EPA), a major n-3 fatty acid in fish oil, on lipopolysaccharide (LPS)-stimulated activation of AP-1 were investigated in human monocytic THP-1 cells. The results demonstrated that AP-1 DNA binding activity stimulated by LPS was suppressed by preincubating cells with EPA. Lipopolysaccharide-stimulated increase of c-Jun and c-Fos protein levels was also attenuated by EPA pretreatment. In addition, EPA pretreatment decreased LPS-induced c-Jun phosphorylation and c-Jun N-terminal kinase (JNK) activation. The results suggest that suppression of TNF-alpha expression by EPA may be partly mediated by its inhibitory effect on AP-1 activation.
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PMID:Eicosapentaenoic acid prevents lipopolysaccharide-stimulated DNA binding of activator protein-1 and c-Jun N-terminal kinase activity. 1568 Nov 65

In Alzheimer's disease (AD), one finds increased presence of monocytes/macrophages and activated microglial cells in the brain. Immunohistochemical studies show increased expression of chemokine receptor 5 (CCR5) on reactive microglia associated with amyloid deposits in AD, suggesting that CCR5 may play a role in the regulation of the immune response in AD. In this study, we used peripheral blood monocytes and human monocytic THP-1 cell line as a model of microglia to delineate the cellular signaling mechanism of Abeta-induced CCR5 expression and the latter's role in the chemotaxis of monocytes. We observed that Abeta peptides at pathophysiological concentrations (125 nM) increased CCR5 mRNA and cell surface protein expression. The cellular signaling involved activation of c-Raf, ERK-1/ERK-2, and c-Jun NH(2)-terminal kinase. Analysis of some transcription factors associated with CCR5 promoter revealed that Abeta increased DNA binding activity of Egr-1 and AP-1. In addition, we show that CCR5 promoter contains an Egr-1 like consensus sequence GCGGGGGTG as demonstrated by 1) electrophoretic mobility shift assay, 2) transfection studies with truncated CCR5 gene promoter construct, and 3) chromatin immunoprecipitation analysis. Moreover, transfection of Egr-1 siRNA, but not of scrambled Egr-1 siRNA, in THP-1 cells resulted in >75% reduction in both Abeta-mediated CCR5 expression and concomitant chemotaxis to its ligands. We suggest that inhibition of Egr-1 by either Egr-1 siRNA or pharmacological agents may reduce activation of monocytes/microglia and possibly ameliorate the inflammation and progression of AD.
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PMID:Mechanism of amyloid peptide induced CCR5 expression in monocytes and its inhibition by siRNA for Egr-1. 1574 89

Monocytic cells constitute an important defense mechanism against invading pathogens by recognizing conserved pathogens components. The recognition leads to activation of intracellular pathways involving nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinases (MAPK), such as the c-Jun NH2-terminal kinase (JNK), and p38. We show that in vitro infection with Francisella tularensis results in activation of NF-kappaB, phosphorylation of p38 and c-Jun, and secretion of TNF-alpha in adherent mouse peritoneal cells, in the mouse macrophage-like cell line J774A.1, in the human macrophage cell line THP-1, and in human peripheral blood monocytic cells. This occurred after infection with the human live vaccine strain, F. tularensis LVS or a mutant strain denoted deltaiglC, which lacks expression of a 23-kDa protein, or after addition of killed F. tularensis LVS. Addition of purified F. tularensis LPS resulted in no discernible effects on the cells. When the effects were followed up to 5 h, activation persisted in cultures with killed bacteria or infected with the deltaiglC strain. In contrast, the signal transduction activation and secretion of TNF-alpha were down-regulated within the 5h period in mouse peritoneal cells, J774 cells or human peripheral blood mononuclear cells infected with F. tularensis LVS. Together, the results suggest that infection with live F. tularensis LVS bacteria leads to a rapid induction of a proinflammatory response in mouse and human cells but after internalization of bacteria, this response is completely or partly down-regulated in most cell types. This down-regulation does not occur when cells are infected with the mutant deltaiglC.
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PMID:Francisella tularensis LVS initially activates but subsequently down-regulates intracellular signaling and cytokine secretion in mouse monocytic and human peripheral blood mononuclear cells. 1592 73

We have reported previously that interleukin-1 and tumor necrosis factor (TNF)-alpha increase expression and function of adenosine A2A receptors (A2ARs), although the increased function is disproportionate to the increment in expression. We therefore studied the effect of TNF-alpha on A2A R function and desensitization in human monocytoid THP-1 cells. We observed that TNF-alpha regulates activity of A2A Rs and other G protein-coupled receptors (GPCRs) by altering their ligand-mediated desensitization. Pretreatment of resting cells with the A2AR agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680) or the pan-adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine quickly desensitized cAMP responses to CGS 21680 restimulation, but TNF-alpha treatment prevented A2AR desensitization. As expected, A2A R occupancy induced translocation of GPCR kinase-2 (GRK2) to the plasma membrane (PM). We were surprised to find that after TNF-alpha treatment, A2AR occupancy not only failed to induce GRK2 translocation to PM but also decreased GRK2 association with PM. TNF-alpha altered GRK2 translocation in response to the beta-adrenergic receptor agonist isoproterenol in a similar manner. Similar to GRK2, beta-arrestin associated with PM after A2A R stimulation in control cells but not in TNF-alpha-treated cells. C2-ceramide, a downstream mediator in the sphingomyelinase (SMase)-dependent pathway, mimicked the effect of TNF-alpha on GRK2 translocation. Moreover, inhibitors of the SMases and an inhibitor of c-Jun NH2-terminal kinase, also a downstream effector in the SMase pathway, reversed TNF-alpha-mediated effects on GRK2 translocation and A2A R desensitization. These results suggest a novel form of cross-talk between TNF-alpha receptors and GPCRs; TNF-alpha enhances GPCR function by preventing agonist-induced desensitization of GPCRs by diminishing agonist-dependent recruitment of GRK2 and beta-arrestin to PM by a SMase pathway-mediated mechanism.
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PMID:Tumor necrosis factor-alpha prevents desensitization of Galphas-coupled receptors by regulating GRK2 association with the plasma membrane. 1638 76

Hypothalamic astrocytes secrete TGF-beta and 3 alpha,5 alpha-tetrahydro progesterone (3 alpha,5 alpha-THP) in culture. When the astrocyte-conditioned medium (ACM) was incubated with the hypothalamic cell line GT1-7, it resulted in the secretion of GnRH. Immunoneutralization with TGF-beta antibody or ultra-filteration with a 10 kDa cut off filter resulted in attenuation of the GnRH releasing ability of ACM, indicating that TGF-beta was a major factor involved with GnRH release. Treatment with estrogens increases TGF-beta secretion. These observations indicate a significant role of astrocytes in GnRH secretion. Serum-deprivation results in the death of GT1-7 neurons in culture and addition of ACM or TGF-beta to the culture, attenuates cell death. The mechanism of protection from cell death appears to involve phosphorylation of MKK4, JNK, c-Jun(Ser63), and enhancement of AP-1 binding. Co-administration of JNK inhibitors, but not MEK inhibitors attenuated ACM or TGF-beta-induced c-Jun(Ser63) phosphorylation and their neuroprotective effects. These studies suggest that astrocytes can protect neurons, at least in part, by the release of TGF-beta and activation of a c-Jun/AP-1 protective pathway.
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PMID:Role of astrocytes in reproduction and neuroprotection. 1638 90

Unregulated uptake of oxidized low-density lipoproteins (ox-LDL) via macrophage scavenger receptors (SRs) such as lectin-like ox-LDL receptor-1 (LOX-1) is a key event in atherosclerosis. In this study, we examined the effects of five selected food phytochemicals on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced LOX-1 mRNA expression in THP-1 human monocyte-like cells. Nobiletin, a citrus polymethoxylated flavone, markedly reduced it in dose- and time-dependent manners. It also suppressed the phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2, c-Jun NH2-terminal kinase (JNK) 1/2, and c-Jun (Ser-63), thereby inhibiting the transcriptional activity of activator protein-1. Further nobiletin attenuated expression of SR-A, SR-PSOX, CD36, and CD68, but not CLA-1, mRNA, leading to the blockade of DiI-acLDL uptake. Together, our results suggest that nobiletin is a promising phytochemical for regulating atherosclerosis with reasonable action mechanisms.
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PMID:Nobiletin, a citrus flavonoid, suppresses phorbol ester-induced expression of multiple scavenger receptor genes in THP-1 human monocytic cells. 1669 17


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