Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Curcumin has been shown to exhibit anti-inflammatory, antimutagenic, and anticarcinogenic activities. However, the modulatory effect of curcumin on the functional activation of primary microglial cells, brain mononuclear phagocytes causing the neuronal damage, largely remains unknown. The current study examined whether curcumin influenced NO production in rat primary microglia and investigated its underlying signaling pathways. Curcumin decreased NO production in LPS-stimulated microglial cells in a dose-dependent manner, with an IC(50) value of 3.7 microM. It also suppressed both mRNA and protein levels of inducible nitric oxide synthase (iNOS), indicating that this drug may affect iNOS gene expression process. Indeed, curcumin altered biochemical patterns induced by LPS such as phosphorylation of all mitogen-activated protein kinases (MAPKs), and DNA binding activities of nuclear factor-kappaB (NF-kappaB) and activator protein (AP)-1, assessed by reporter gene assay. By analysis of inhibitory features of specific MAPK inhibitors, a series of signaling cascades including c-Jun N-terminal kinase (JNK), p38 and NF-kappaB was found to play a critical role in curcumin-mediated NO inhibition in microglial cells. The current results suggest that curcumin is a promising agent for the prevention and treatment of both NO and microglial cell-mediated neurodegenerative disorders.
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PMID:Inhibitory effect of curcumin on nitric oxide production from lipopolysaccharide-activated primary microglia. 1693 99

Inflammation plays an essential role in vascular injury and repair. Mononuclear phagocytes are important contributors in these processes, in part, via adhesive interactions and secretion of proinflammatory cytokines. The antiinflammatory cytokine interleukin (IL)-10 suppresses such responses via deactivation of monocytes/macrophages and repression of inflammatory cytokine expression. The mechanisms of IL-10's suppressive action are, however, incompletely characterized. Here, we report that systemic IL-10 treatment after carotid artery denudation in mice blunts inflammatory cell infiltration and arterial tumor necrosis factor (TNF) expression. At the molecular level, in a human monocytic cell line, U937 IL-10 suppressed LPS-induced mRNA expression of a number of inflammatory cytokines, mainly via posttranscriptional mRNA destabilization. Detailed studies on IL-10 regulation of TNF-alpha mRNA expression identified AU-rich elements (ARE) in the 3' untranslated region as a necessary determinant of IL-10-mediated TNF-alpha mRNA destabilization. IL-10 sensitivity to TNF depends on the ability of IL-10 to inhibit the expression and mRNA-stabilizing protein HuR and via IL-10 mediated repression of p38 mitogen-activated protein (MAP) kinase activation. Because IL-10 function and signaling are important components for control of inflammatory responses, these results may provide insights necessary to develop strategies for modulating vascular repair and other accelerated arteriopathies, including transplant vasculopathy and vein graft hyperplasia.
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PMID:IL-10-induced TNF-alpha mRNA destabilization is mediated via IL-10 suppression of p38 MAP kinase activation and inhibition of HuR expression. 1693 32

In healthy hosts, acute infection with the opportunistic pathogen Toxoplasma gondii is controlled by innate production of IL-12, a key cytokine crucial for the development of protective immunity. Previous work has established that the mitogen-activated protein kinases (MAPK), particularly p38 and ERK1/2, are important regulators of T. gondii-induced IL-12 synthesis. Here we report that host cell Ca(2+) is required for activation of MAPK by T. gondii, as well as LPS and CpG, and for parasite-induced synthesis of IL-12. In addition, pharmacological mobilization of Ca(2+) stores in macrophages treated with parasites or LPS enhanced MAPK phosphorylation initiated by these stimuli. Investigation of the upstream mechanism by which Ca(2+) regulates MAPK activation revealed that T. gondii induced acute activation of conventional, Ca(2+)-dependent PKCalpha and PKCbeta, which are required for infection-induced MAPK activation and production of IL-12. Despite these findings, neither acute parasite infection nor LPS initiated a measurable Ca(2+) response in macrophages, suggesting that low levels of Ca(2+) are permissive for initiation of pro-inflammatory signaling. Together these data identify host cell Ca(2+) and PKC as crucial regulators of the innate immune response to microbial stimuli, including T. gondii.
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PMID:Host cell Ca2+ and protein kinase C regulate innate recognition of Toxoplasma gondii. 1707 36

Severe injury deranges immune function and increases the risk of sepsis and multiple organ failure. Kupffer cells play a major role in mediating posttraumatic immune responses, in part via different Toll-like receptors (TLR). Although mitogen-activated protein kinases (MAPK) are key elements in the TLR signaling pathway, it remains unclear whether the activation of different MAPK are TLR specific. Male C3H/HeN mice underwent midline laparotomy (i.e., soft tissue injury), hemorrhagic shock (MAP approximately 35 mm Hg for 90 min), and resuscitation. Kupffer cells were isolated 2 h thereafter, lysed and immunoblotted with antibodies to p38, ERK1/2, or JNK proteins. In addition, cells were preincubated with specific inhibitors of p38, ERK1/2, or JNK MAPK followed by stimulation with the TLR2 agonist, zymosan; the TLR4 agonist, LPS; or the TLR9 agonist, CpG DNA. Cytokine (TNF-alpha, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and KC) production was determined by cytometric bead array after 24 h in culture. MAPK activity as well as TNF-alpha, MCP-1, and KC production by Kupffer cells were significantly increased following trauma-hemorrhage. TLR4 activation by LPS stimulation increased the levels of all measured cytokines. CpG-stimulated TLR9 signaling increased TNF-alpha and IL-6 levels; however, it had no effect on chemokine production. Selective MAPK inhibition demonstrated that chemokine production was mediated via p38 and JNK MAPK activation in TLR2, -4, and -9 signaling. In contrast, TNF-alpha and IL-6 production was differentially regulated by MAPK depending on the TLR pathway stimulated. Thus, Kupffer cell TLR signaling employs different MAPK pathways in eliciting cytokine and chemokine responses following trauma-hemorrhage.
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PMID:The role of MAPK in Kupffer cell toll-like receptor (TLR) 2-, TLR4-, and TLR9-mediated signaling following trauma-hemorrhage. 1711 77

Signal transducer and activator of transcription 3 (STAT3) has been shown to mediate the anti-inflammatory effect of IL-10. Activated STAT3 suppresses LPS-induced IL-6, tumor necrosis factor-alpha and IL-12 gene expression in macrophages and dendritic cells. However, the mechanism of Toll-like receptor (TLR) signal suppression by STAT3 has not been clarified. In this study, we investigated the effect of constitutively activated STAT3 (STAT3C) on LPS-induced nuclear factor-kappaB (NF-kappaB) activation. The forced expression of STAT3C in HEK293/TLR4 cells, but neither wild-type STAT3 nor dominant-negative form of STAT3, suppressed LPS-TLR4-mediated NF-kappaB reporter activation. The over-expression of STAT3C did not affect the signal transduction of TLR4, such as the phosphorylation of inhibitory nuclear factor-kappaBalpha and mitogen-activated protein kinases and the DNA-binding activity of NF-kappaB. Thus, STAT3C could suppress the transcriptional and/or translational activity of NF-kappaB. To define the molecular mechanism, we searched STAT3C-binding proteins by using a proteomic approach and found that a novel RNA-binding protein, alphaCP-1, interacted with STAT3C. alphaCP-1 is a K-homology domain-containing RNA-binding protein with specificity for C-rich pyrimidine tracts. Such proteins play pivotal roles in a broad-spectrum of transcriptional and translational events. The over-expression of alphaCP-1 augmented the suppressive effect of STAT3C on NF-kappaB activation in HEK293/TLR4 cells. Furthermore, the forced expression of alphaCP-1 enhanced the antagonistic effect of IL-10 on IL-6 production in RAW264.7 cells, while small interfering RNA against alphaCP-1 reduced it. These data suggest that alphaCP-1 is involved in the STAT3-mediated suppression of NF-kappaB activity.
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PMID:An RNA-binding protein alphaCP-1 is involved in the STAT3-mediated suppression of NF-kappaB transcriptional activity. 1738 69

Glucosamine supplements are very promising nonsteroidal anti-inflammatory agents widely used for the treatment of arthritis in animals and humans. In this study, we have proposed the molecular mechanism underlying the anti-inflammatory properties of glucosamine hydrochloride (GLN) using mouse macrophage cell line (RAW 264.7). Treatment with GLN inhibited LPS-stimulated nitric oxide (NO) production. Western blotting and RT-PCR analysis showed that GLN treatment decreased LPS-induced inducible nitric-oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein and mRNA expression in RAW 264.7 cells, respectively. To further elucidate the mechanism of inhibitory effect of GLN, we studied the LPS-induced phosphorylation of mitogen-activated protein kinases (pp44/42 and pp38). Our results clearly indicated that GLN treatment resulted in a reduction of pp38, whereas activation of p44/42 was not affected. In addition, LPS-induced activation of nuclear factor-kappaB (NF-kappaB) DNA binding suggests an inhibitory effect of GLN. These results indicate that GLN suppresses the LPS-induced production of NO, expression of iNOS and COX-2 by inhibiting NF-kappaB activation and phosphorylation of p38 MAP kinase.
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PMID:Glucosamine inhibits LPS-induced COX-2 and iNOS expression in mouse macrophage cells (RAW 264.7) by inhibition of p38-MAP kinase and transcription factor NF-kappaB. 1744 Sep 93

Alpha-galactosylceramide (alpha-GalCer), a bioactive glycolipid isolated from the marine sponge Agelas mauritianus, is a potent immunomodulator with therapeutic potential for the treatment of autoimmune diseases and cancer. The Toll-like receptor 4 (TLR4), one of the promising molecular targets for immune-modulating drugs, is commonly expressed in innate immune cells especially macrophages and dendritic cells. Currently, whether alpha-GalCer can activate TLR4 signaling pathways remains unreported. In this study, we examined the effects of alpha-GalCer and its various structural analogs, CCL-1 approximately 47, on TLR4 activation. We found that one alpha-GalCer analog (CCL-34), but not alpha-GalCer itself, strongly stimulated NF-kappaB activity in RAW 264.7 cells. CCL-34 activated NF-kappaB in a TLR4-dependent manner and stimulated TNF-alpha production in bone marrow cells of TLR4-functional C3H/HeN mice but not in those of TLR4-defective C3H/HeJ mice. Furthermore, CCL-34 treatment stimulated NF-kappaB activation and IL-8 production in a 293 cell line constitutively expressing human TLR4, MD-2 and CD14. Treatment of RAW 264.7 cells with CCL-34 also activated TLR4-downstream mitogen-activated protein kinases (ERK, JNK and p38), induced expression of TLR4-downstream genes (TNF-alpha, IL-6, IL-1beta and iNOS) and promoted production of cytokines characteristic of activated macrophages. CCL-34-treated RAW 264.7 cells acquired a distinct morphology similar to that of LPS-activated macrophages and exhibited higher phagocytotic activity. Moreover, treatment with a TLR4-neutalizing antibody inhibited the CCL-34-induced morphological alteration. In summary, we identify a novel synthetic compound CCL-34 that can activate macrophages via TLR4-dependent signaling pathways. Our results suggest that CCL-34 is an immune modulator and may serve as a potential drug lead for immunotherapy.
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PMID:A synthetic analog of alpha-galactosylceramide induces macrophage activation via the TLR4-signaling pathways. 1744 76

We have previously reported that a well-characterized glycoprotein fraction containing fucose residues in an extract of Ganoderma lucidum polysaccharides (EORP) exerts certain immuno-modulation activity by stimulating the expression of inflammatory cytokines via TLR4. Continuing our studies, we have demonstrated that EORP increases the surface expression of CD14 and TLR4 within murine macrophages J774A.1 cells in vitro, and further promotes LPS binding and uptake by J774A.1 cells in a CD14-dependent fashion. Moreover, we observed the co-localization of internalized LPS with lysosome- and Golgi-apparatus markers within 5 min after J774A.1 cells stimulated with LPS. In addition, EORP pretreatment of J774A.1 cells and human blood-derived primary macrophages, followed by LPS stimulation, results in the super-induction of interleukin-1beta (IL-1) expression. Endocytosis inhibitors: such as cytochalasin D and colchicine effectively block EORP-enhanced LPS internalization by J774A.1 cells; yet they fail to decrease the LPS-induced phosphorylation of certain mitogen-activated protein kinases, and IL-1 mRNA and proIL-1 protein expression, indicating that LPS internalization by J774A.1 cells is not associated with LPS-dependent activation. Our current results could provide a potential EORP-associated protection mechanism for bacteria infection by enhancing IL-1 expression and the clearance of contaminated LPS by macrophages.
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PMID:Ganoderma lucidum polysaccharides enhance CD14 endocytosis of LPS and promote TLR4 signal transduction of cytokine expression. 1747 83

Histamine is an important mediator in immune responses, but it is unclear whether periodontal tissues express histamine receptors and are able to respond to histamine. We hypothesized that histamine, inflammatory cytokines, and bacterial components released in inflamed periodontal tissues may be synergistically involved in periodontitis. The present study showed that human gingival fibroblasts mainly express histamine receptor H1R, and responded to histamine to produce interleukin (IL)-8. Stimulation of gingival fibroblasts with tumor necrosis factor-alpha, IL-1alpha, and lipopolysaccharide markedly induced IL-8 production, and the IL-8 production was synergistically augmented in the presence of or pre-treatment with histamine. Selective inhibitors of mitogen-activated protein kinases (MAPKs), nuclear factor (NF)-kappaB, and phospholipase C (PLC) significantly inhibited the synergistic effect. These results indicate that histamine induces IL-8 production from gingival fibroblasts through H1R, and synergistically augments the inflammatory stimuli by amplification of the MAPK and NF-kappaB through H1R-linked PLC. Abbreviations used: HDC, histidine decarboxylase; LPS, lipopolysaccharide; IL, interleukin; TNF, tumor necrosis factor; HR, histamine receptor; PLC, phospholipase C; MAPK, mitogen-activated protein kinase; NF, nuclear factor; ERK, extracellular signal-related kinase; JNK, c-Jun N-terminal kinase; R, receptor; TLR, Toll-like receptor; alpha-MEM, alpha-minimum essential medium; FCS, fetal calf serum; RT-PCR, reverse-transcriptase polymerase chain-reaction; ELISA, enzyme-linked immunosorbent assay; SD, standard deviation; LDH, lactate dehydrogenase.
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PMID:Histamine amplifies immune response of gingival fibroblasts. 1795 1

Toll-like receptors (TLRs) response is critical in innate resistance to infection. Alcohol consumption has been shown to suppress the inflammatory response mediated through TLR4, down regulating the production of inflammatory cytokines. We recently reported that low concentrations of ethanol activate TLR4 signaling in astrocytes and triggers neuroinflammation. Because macrophages are important cells in innate immunity, we investigate whether low concentrations of ethanol could stimulate the TLR4 signaling response in murine RAW 264.7 macrophages, and the mechanism involved in the ethanol-induced TLR4 activation. Our results show that while ethanol, at high concentrations (100mM) or in the presence of the LPS, suppresses the TLR4 response, low to moderate levels (10-50mM) activate the TLR4 response and triggers the stimulation of the mitogen-activated protein kinases (MAPKs) and the transcription factor NF-kappaB pathways, leading to the production of nitric oxide (NO) and inflammatory cytokines. Pre-treatment with anti-TLR4 Abs abolishes the effects of ethanol on the production of cytokines. We also present evidence that stimulation with either ethanol or LPS induces translocation and clustering of TLR4 and signaling molecules (IRAK and MAPKs) into lipid rafts. Treatment with either streptolysin-O or saponin, lipid rafts disrupting agents, abolishes the ethanol-induced activation of the TLR4/IL-1RI signaling pathway. In summary, the present results demonstrate that low to moderate concentrations of ethanol are capable of stimulating TLR4/IL-1RI response, and provide evidence of a novel mechanism by which ethanol, through its interaction with membrane rafts, can promote TLR4/IL-1RI recruitment and signaling.
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PMID:Lipid rafts regulate ethanol-induced activation of TLR4 signaling in murine macrophages. 1806 74


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