Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.11.18 (MAP)
7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipopolysaccharide (LPS) and muramyl dipeptide (MDP) are components of bacterial cell walls that cause innate immune responses and inflammation. Toll-like receptor 4 (TLR4) is a receptor for LPS and transduces signals through myeloid differentiation factor 88 (MyD88), which plays essential roles in the TLR/interleukin (IL)-1R signaling and activates MAP/ERK kinase (MEK)/ERK pathway to induce receptor activator of NF-kappaB ligand (RANKL) expression in osteoblasts. Osteoblasts express nucleotide oligomerization domain (NOD)2, an intracellular sensor for MDP, in response to LPS, IL-1 and TNF. NOD2 binds receptor-interacting protein (RIP2), a serine/threonine kinase which transduces NF-kappaB signaling. MDP synergistically enhances osteoclast formation induced by LPS, IL-1 and TNF through RANK ligand up-regulation in osteoblasts. TLR4 and NOD2 recognize bacterial components on cell surfaces and inside cells, respectively, and these signals up-regulate RANKL expression in osteoblasts, which results in enhancing osteoclast formation and function.
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PMID:[Bone destruction caused by osteoclasts]. 1646 24

We have examined whether toll-like receptor (TLR)2-mediated stimulation by macrophage-activating lipopeptide-2 (MALP-2), originally purified from Mycoplasma fermentans, induces cyclooxygenase (COX)-2 and prostaglandin (PG)E(2) in human placental trophoblast cells. The signaling mechanism by which MALP-2 exerts its effect has also been examined. Human placental trophoblast cells isolated from term placenta were used. TLR expression in trophoblast cells was confirmed by multiplex PCR and immunocytochemistry, and examined whether MALP-2 induces COX-2 and PGE(2) by Northern blotting, RT-PCR, Western blotting and ELISA, respectively. The activation of NF-kappaB and MAP kinases (ERK1/2 and p38) was examined by Western blotting. The effects of inhibitors of NF-kappaB, MEK1/2 and p38 on MALP-2-induced PGE(2) production were also evaluated. TLR2, TLR6 and TLR4 were expressed in human placental trophoblast cells. MALP-2 significantly induced COX-2 expression and enhanced PGE(2) production in a dose-dependent manner. MALP-2 induced the activation of NF-kappaB, ERK1/2 and p38 MAPK. Inhibitors of NF-kappaB, MEK1/2 and p38 blocked MALP-2-inducible PGE(2) production. TLR2-mediated stimulation by MALP-2 induces COX-2 and PGE(2) in human placental trophoblast cells via NF-kappaB and MAP kinases pathways.
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PMID:Macrophage-activating lipopeptide-2 induces cyclooxygenase-2 and prostaglandin E(2) via toll-like receptor 2 in human placental trophoblast cells. 1660 Mar 83

Erosive osteolysis induced by implant-derived wear debris is mediated by recruitment and activation of osteoclasts in a pro-inflammatory microenvironment that is enriched with osteoclastogenic and pro-inflammatory cytokines such as RANKL and tumor necrosis factor alpha (TNF-alpha). These cytokines activate the transcription factor NF-kappaB and MAP kinases, including c-Jun, Erks, and p38, all known to be essential for the development of osteoclasts. We have recently documented that TNF and RANKL play a pivotal role in the development of inflammatory osteolysis. We have also found that polymethyl methacrylate (PMMA) particles stimulate osteoclastogenesis, at least in part, by induction of RANKL, TNF, and by activation of NF-kappaB and MAP kinases. More importantly, our data indicate that inhibitors of NF-kappaB and the MAP kinases p38 and ERK abrogate particle-induced osteoclastogenesis. In the current study, we investigated if inhibition of c-Jun N-Terminal kinase (JNK) pathway alters PMMA-induced osteoclastogenesis. Our findings point out that PMMA particles activate the JNK pathway in wild-type and TLR4-null (endotoxin-resistant) osteoclast precursors. This activation was selectively blocked in a dose-dependent fashion by the JNK inhibitor SP600125. Most importantly, we provide evidence that SP600125 inhibits osteoclast formation in a reversible manner. Collectively, our findings demonstrate that activation of the JNK pathway is essential for basal and PMMA-stimulated osteoclastogenesis, and buttress the potential significance of targeting the JNK pathway to inhibit osteolysis.
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PMID:Map kinase c-JUN N-terminal kinase mediates PMMA induction of osteoclasts. 1673 13

In contrast to the role of lipopolysaccharide from Gram-negative bacteria, the role of Gram-positive bacterial components in inducing inflammation in the CNS remains controversial. We studied the potency of highly purified lipoteichoic acid and muramyl dipeptide isolated from Staphylococcus aureus to activate primary cultures of rat microglia. Exposure of pure microglial cultures to lipoteichoic acid triggered a significant time- and dose-dependent production of pro-inflammatory cytokines (tumour-necrosis factor-alpha, interleukin-1beta, interleukin-6) and nitric oxide. Muramyl dipeptide strongly and selectively potentiated lipoteichoic acid-induced inducible nitric oxide synthase expression and nitric oxide production. However, it did not have any significant influence on the production of pro-inflammatory cytokines. As bacterial components are recognised by the innate immunity through Toll-like receptors (TLRs) we showed that lipoteichoic acid was recognised in microglia by the TLR2 and lipopolysaccharide by the TLR4, as cells isolated from mice lacking TLR2 or TLR4 did not produce pro-inflammatory cytokines and nitric oxide upon lipoteichoic acid or lipopolysaccharide stimulation, respectively. Lipoteichoic acid-induced glia activation was mediated by p38 and ERK1/2 MAP kinases, as pretreatment with inhibitor of p38 or ERK1/2 decreased lipoteichoic acid-induced cytokine release, iNOS mRNA expression and nitric oxide production. The observed pro-inflammatory response induced by lipoteichoic acid-activated microglia could play a major role in the inflammatory response of CNS induced by Gram-positive bacteria.
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PMID:Highly purified lipoteichoic acid induced pro-inflammatory signalling in primary culture of rat microglia through Toll-like receptor 2: selective potentiation of nitric oxide production by muramyl dipeptide. 1687 8

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

Modulation of macrophage/dendritic cell (DC) cytokine production by the filarial nematode phosphorylcholine (PC)-containing product, ES-62, is mediated by Toll-like receptor (TLR) 4 and signal transduction depends on the TLR adaptor MyD88. Intriguingly, comparison of TLR4 knock-out (ko) mice with TLR4 mutant C3H/HeJ mice indicates that ES-62 cytokine responses are not dependent on the Pro712 residue of TLR4, which is crucial for the response to bacterial lipopolysaccharide (LPS). Because other immunomodulatory effects of ES-62 have been attributed to PC we have now investigated, using PC conjugated to ovalbumin (PC-Ova), whether PC is responsible for the interaction of ES-62 with TLR4. PC-Ova mimicked the modulation of interleukin (IL)-12 production by ES-62 in a TLR4- and MyD88-dependent manner and as with native ES-62, PC-Ova effects were not dependent on Pro712. Furthermore, both native ES-62 and PC-Ova suppressed Akt phosphorylation, whereas neither altered the activation of p38 or Erk MAP kinases. To rule out any role for the ES-62 protein component, we tested a PC-free recombinant ES-62 (rES-62) generated in the yeast Pichia pastoris. Surprisingly, rES-62 also modulated IL-12 production, but in a TLR4/MyD88-independent manner. Furthermore, rES-62 strongly activated both the p38 and Erk MAP kinases and Akt. However, recent biophysical analysis suggests there are differences in folding/shape between native and rES-62 and hence data obtained with the latter should be treated with caution. Nevertheless, although our study indicates that PC is likely to be primarily responsible for the modulation of cytokine production observed with native ES-62, an immunomodulatory role for the protein component cannot be ruled out.
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PMID:Phosphorylcholine mimics the effects of ES-62 on macrophages and dendritic cells. 1726 40

In macrophages and monocytes, microbial components trigger the production of pro-inflammatory cytokine through Toll-like receptors (TLRs). Although major TLR signaling pathways are mediated by serine/threonine kinases, including TAK1, IKK and MAP kinases, tyrosine phosphorylation of intracellular proteins by TLR ligands has been suggested in a number of reports. Here, we demonstrated that peptidoglycan (PGN) of a Gram-positive bacterial cell wall component, a TLR2 ligand and lipopoysaccharide (LPS) of a Gram-positive bacterial component, a TLR4 ligand induced tyrosine phosphorylation of phospholipase Cgamma-2 (PLCgamma2), leading to intracellular free Ca2+ mobilization in bone marrow-derived macrophages (BMMphi) and bone marrow-derived dendritic cells (BMDC). PGN- and LPS-induced Ca2+ mobilization was not observed in BMDC from PLCgamma2 knockout mice. Thus, PLCgamma2 is essential for TLR2 and TLR4-mediated Ca2+ flux. In PLCgamma2-knockdown cells, PGN-induced IkappaB-alpha phosphorylation and p38 activation were reduced. Moreover, PLCgamma2 was necessary for the full production of TNF-alpha and IL-6. These data indicate that the PLCgamma2 pathway plays an important role in bacterial ligands-induced activation of macrophages and dendritic cells.
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PMID:Peptidoglycan and lipopolysaccharide activate PLCgamma2, leading to enhanced cytokine production in macrophages and dendritic cells. 1823 61

DiC14-amidine cationic liposomes were recently shown to promote Th1 responses when mixed with allergen. To further define the mode of action of diC14-amidine as potential vaccine adjuvant, we characterized its effects on mouse and human myeloid dendritic cells (DC). First, we observed that, as compared with two other cationic liposomes, only diC14-amidine liposomes induced the production of IL-12p40 and TNF-alpha by mouse bone marrow-derived DC. DiC14-amidine liposomes also activated human DC, as shown by synthesis of IL-12p40 and TNF-alpha, accumulation of IL-6, IFN-beta and CXCL10 mRNA, and up-regulation of membrane expression of CD80 and CD86. DC stimulation by diC14-amidine liposomes was associated with activation of NF-kappaB, ERK1/2, JNK and p38 MAP kinases. Finally, we demonstrated in mouse and human cells that diC14-amidine liposomes use Toll-like receptor 4 to elicit both MyD88-dependent and Toll/IL-1R-containing adaptor inducing interferon IFN-beta (TRIF)-dependent responses.
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PMID:DiC14-amidine cationic liposomes stimulate myeloid dendritic cells through Toll-like receptor 4. 1838 79

Phagocytosis and subsequent degradation of pathogens by macrophages play a pivotal role in host innate immune responses to microbial infection. Recent studies have shown that Toll-like receptors (TLRs) play an important role in promoting the clearance of bacteria by up-regulating the phagocytic activity of macrophages. However, information regarding the signaling mechanism of TLR-mediated phagocytosis is still limited. Here, we provide evidence that the stimulation of TLR4 with LPS leads to activation of multiple signaling pathways including MAP kinases, phosphatidylinositide 3-kinase (PI3K), and small GTPases in the murine macrophage-like cell line RAW264.7. Specific inhibition of Cdc42/Rac or p38 MAP kinase, but not PI3K, reduced TLR4-induced phagocytosis of bacteria. Moreover, we have found that either inhibition of actin polymerization by cytochalasin D or the knockdown of actin by RNAi markedly reduced the activation of Cdc42 and Rac by LPS. TLR4-induced activation of Cdc42 and Rac appears to be independent of MyD88. Taken together, our results described a novel actin-Cdc42/Rac pathway through which TLRs can specifically provoke phagocytosis.
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PMID:MyD88-independent activation of a novel actin-Cdc42/Rac pathway is required for Toll-like receptor-stimulated phagocytosis. 1859 1

The assembly of a collection of gene-expression signatures of the major types of B-cell non-Hodgkin's lymphoma has identified increased T-cell leukemia/lymphoma 1A (TCL1) expression in multiple lymphoma types and cases, and has enabled the investigation of the functional and clinical importance of TCL1 expression. Specifically, Burkitt's lymphoma cases show a homogeneously strong expression of TCL1, whereas diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, nodal marginal zone lymphoma, and splenic marginal zone lymphoma display a striking variability in the intensity of TCL1 staining. This was validated in two independent series. A Gene-Set Enrichment Analysis of the genes correlated with TCL1A expression found that variation in the level of expression of TCL1A was significantly associated with some of the most important gene signatures recognizing B-cell lymphoma pathogenesis and heterogeneity, such as germinal center, B-cell receptor, NF-kappaB (and its target genes), death, MAP kinases, TNFR1, TOLL, and IL1R. Additionally, TCL1 expression was correlated with shorter time to treatment in chronic lymphocytic leukemia cases and shorter lymphoma-specific survival in mantle cell lymphoma series, thus indicating the clinical and biological significance of TCL1 expression, and suggesting TCL1A as a potential therapeutic target.
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PMID:TCL1A expression delineates biological and clinical variability in B-cell lymphoma. 1882 Jun 75


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