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

Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in heme degradation, protects against oxidative stress, and shows potent anti-inflammatory effects. Oxidized phospholipids, which are generated during inflammation and apoptosis, modulate the inflammatory response by inducing the expression of several genes including HO-1. Here we investigated the signaling pathways and transcriptional events involved in the induction of HO-1 gene expression by oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC) in human umbilical vein endothelial cells. OxPAPC up-regulated HO-1 mRNA and protein in a time- and concentration-dependent manner, whereas pro-inflammatory agents like TNF-alpha and lipopolysaccharide did not significantly induce HO-1 expression in human umbilical vein endothelial cells. Signaling pathways involved in the OxPAPC-mediated HO-1 induction included protein kinases A and C, as well as the mitogen-activated protein kinases p38 and ERK. The cAMP-responsive element-binding protein (CREB) was phosphorylated via these pathways in response to OxPAPC treatment and expression of a dominant-negative mutant of CREB inhibited OxPAPC-induced activity of a human heme oxygenase-1 promoter-driven luciferase reporter construct. We identified a cAMP-responsive element and a Maf recognition element to be involved in the transcriptional activation of the HO-1 promoter by OxPAPC. In gel shift assays we observed binding of CREB to the cAMP-responsive element after OxPAPC treatment. Induction of HO-1 expression by lipid oxidation products via CREB may represent a feedback mechanism to limit inflammation and associated tissue damage.
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PMID:Oxidized phospholipids induce expression of human heme oxygenase-1 involving activation of cAMP-responsive element-binding protein. 1452 7

Dendritic cells (DCs) are recognized as major players in the regulation of immune responses to a variety of Ags, including bacterial agents. LPS, a Gram-negative bacterial cell wall component, has been shown to fully activate DCs both in vitro and in vivo. LPS-induced DC maturation involves activation of p38, extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases, and NF-kappaB. Blocking p38 inhibits LPS-induced maturation of DCs. In this study we investigated the role of LPS in the in vitro generation of immature DCs. We report here that in contrast to the observed beneficial effects on DCs, the presence of LPS in monocyte culture retarded the generation of immature DCs. LPS not only impaired the morphology and reduced the yields of the cultured cells, but also inhibited the up-regulation of surface expression of CD1a, costimulatory and adhesion molecules. Furthermore, LPS up-regulated the secretion of IL-1beta, IL-6, IL-8, IL-10, and TNF-alpha; reduced Ag presentation capacity; and inhibited phosphorylation of ERK, but activated p38, leading to a reduced NF-kappaB activity in treated cells. Neutralizing Ab against IL-10, but not other cytokines, partially blocked the effects of LPS. Inhibiting p38 (by inhibitor SB203580) restored the morphology, phenotype, and Ag presentation capacity of LPS-treated cells. SB203580 also inhibited LPS-induced production of IL-1beta, IL-10, and TNF-alpha; enhanced IL-12 production; and recovered the activity of ERK and NF-kappaB. Thus, our study reveals that LPS has dual effects on DCs that are biologically important: activating existing DCs to initiate an immune response, and inhibiting the generation of new DCs to limit such a response.
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PMID:Novel and detrimental effects of lipopolysaccharide on in vitro generation of immature dendritic cells: involvement of mitogen-activated protein kinase p38. 1456 57

The possible roles of a 14-kDa human thioredoxin (Trx)-related protein (TRP14) in TNF-alpha signaling were studied in comparison with those of Trx1 by RNA interference in HeLa cells. Depletion of TRP14 augmented the TNF-alpha-induced phosphorylation and degradation of I kappa B alpha as well as the consequent activation of NF-kappa B to a greater extent than did Trx1 depletion. Deficiency of TRP14 or Trx1 enhanced TNF-alpha-induced activation of caspases and subsequent apoptosis by a similar extent. The TNF-alpha-induced activation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPKs), however, was promoted by depletion of TRP14 but not by that of Trx1. Unlike Trx1, TRP14 neither associated with nor inhibited the kinase activity of apoptosis signal-regulating kinase-1 (ASK1), an upstream activator of JNK and p38. In combination with the results in the accompanying paper that TRP14 did not reduce the known substrates of Trx1, these results suggest that TRP14 modulates TNF-alpha signaling pathways, provably by interacting with proteins distinct from the targets of Trx1. In an effort to identify target proteins of TRP14, a mutant of TRP14, in which the active site cysteine (Cys(46)) was substituted with serine, was shown to form a disulfide-linked complex with LC8 cytoplasmic dynein light chain. The complex was detected in HeLa cells treated with H(2)O(2) or TNF-alpha but not in untreated cells, suggesting that LC8 cytoplasmic dynein light chain is a possible substrate of TRP14.
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PMID:Roles of TRP14, a thioredoxin-related protein in tumor necrosis factor-alpha signaling pathways. 1460 43

The role of p38 mitogen-activated protein (MAP) kinase in the activation of human neutrophils and repression of TNF-alpha-induced apoptosis in response to plasma opsonized crystals of calcium pyrophosphate dihydrate (CPPD) was investigated. We monitored the endogenous phosphotransferase activity of p38 kinase in neutrophils stimulated with CPPD crystals (25 mg/ml) alone or in the presence of TNF-alpha (10 ng/ml), and with TNF-alpha alone. CPPD crystals induced a 2-fold activation of p38 kinase activity over the basal activity that was observed in untreated neutrophils. Furthermore, CPPD crystals repressed the TNF-alpha associated 6-fold induction of p38 kinase phosphotransferase activity to levels associated with CPPD crystal incubation alone in a PD98059 (20 ng/ml) and Wortmannin (100 nM) sensitive manner. Inhibition of CPPD crystal-induced activation of the neutrophil inflammatory response as measured by chemiluminescence, superoxide anion generation and degranulation as determined by myeloperoxidase and lysozyme release was observed in the presence of the specific p38 MAP kinase inhibitor SB203580 (5 microM). CPPD crystal associated repression of TNF-alpha-induced activation of neutrophil apoptosis as determined by DNA fragmentation correlated with the CPPD crystal mediated inhibition of p38 kinase activity, probably through crystal inhibition of caspase 3. Together, our results indicate that the CPPD crystal associated inflammatory response is regulated through the activation of p38 kinase to sub-apoptotic levels, and that the repression of the TNF-alpha-induced apoptosis program in neutrophils is mediated via the repression of caspase 3 mediated apoptosis-associated p38 kinase activity.
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PMID:Calcium pyrophosphate dihydrate crystal associated induction of neutrophil activation and repression of TNF-alpha-induced apoptosis is mediated by the p38 MAP kinase. 1463 91

Deoxynivalenol (DON, vomitoxin) is a trichothecene mycotoxin that potentially mediates toxicity by upregulating proinflammatory cytokine gene expression in vitro and in vivo. The purpose of this study was to test the hypothesis that DON-induced activation of mitogen-activated protein kinases (MAPKs) mediates transcriptional and posttranscriptional upregulation of TNF-alpha gene expression. RNAse protection assay revealed that DON at 100 to 500 ng/ml induced mRNA expression of TNF-alpha as well as IL-6, IFN-gamma, TGFbeta-1, and TGFbeta-3 and that these effects were potentiated by 100 ng/ml lipopolysaccharide (LPS). DON was found to induce phosphorylation of p38 kinase, extracellular signal-regulated kinases (ERKs), and c-Jun amino terminal kinases (JNKs) in a dose-dependent manner in the RAW 264.7 murine macrophage model. A luciferase reporter gene driven by the murine TNF-alpha promoter was used to assess the role of various MAPKs on DON upregulation of TNF-alpha gene transcription. The p38 inhibitor SB203580 reduced induction of luciferase activity by DON, LPS, and DON + LPS. In addition, the ERK inhibitor PD 98059 blocked DON- and DON + LPS-induced luciferase activity whereas the JNK inhibitor impaired LPS- and DON + LPS-induced luciferase activity. To study the effects of MAPKs on DON-induced TNF-alpha mRNA stability, an asynchronous model was used whereby cells were pretreated with LPS for 4 h and the medium was removed. Following incubation with medium containing a transcription inhibitor, 5,6-dichloro-beta-D-ribofuranosyl-benzimidazole, MAPK inhibitors and/or DON (250 ng/ml) cultures were monitored for TNF-alpha mRNA expression. DON-induced TNF-alpha mRNA stabilization was abrogated in the presence of SB 203580, whereas the stabilization by DON was not affected by PD 98059 or SP 600125. To verify the role of MAPKs in DON + LPS-induced TNF-alpha production, cells were incubated with LPS, DON, or LPS + DON for 18 h in the presence of inhibitors. ELISA of supernatant indicated that induction of TNF-alpha production by DON alone was significantly reduced by SB 203580 and PD 98059, whereas all three inhibitors blocked LPS- and DON + LPS-induced TNF-alpha production. Taken together, these results suggest that relative to DON-induced TNF-alpha mRNA expression, p38 and ERK activation contribute to DON-induced transcriptional upregulation whereas p38 plays a role in increasing mRNA stability.
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PMID:Transcriptional and posttranscriptional roles for p38 mitogen-activated protein kinase in upregulation of TNF-alpha expression by deoxynivalenol (vomitoxin). 1464 21

We have studied the effects of ITIM-bearing FcgammaRIIB2 on the FcepsilonRI-dependent nuclear shuttling of mitogen-activated protein (MAP) kinase (ERK2) in rat basophilic leukemia (RBL-2H3) cells. The cross-linking of FcepsilonRI elicited the sustained increase of the intracellular calcium ion concentration ([Ca(2+)](i)) and the translocation of ERK2 from the cytoplasm to the nucleus. The import of ERK2 to the nucleus reached the maximum at 6-7 min, thereafter ERK2 was exported within 30 min. The co-clustering of FcepsilonRI and FcgammaRIIB2 increased the [Ca(2+)](i) and induced the import of ERK2. However, the calcium increase was transient and ERK2 was rapidly exported to the cytoplasm. In addition, the phosphorylation of ERK2 and the production of TNF-alpha were decreased in case of co-clustering of FcepsilonRI and FcgammaRIIB2. This suggested that the co-clustering negatively control the production of pro-inflammatory cytokines through the suppression of nuclear shuttling of ERK2.
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PMID:The effects of ITIM-bearing FcgammaRIIB on the nuclear shuttling of MAP kinase in RBL-2H3 cells. 1468 21

Osteopontin (OPN), also called cytokine Eta-1, expressed in the myocardium co-incident with heart failure plays an important role in post myocardial infarction (MI) remodeling by promoting collagen synthesis and accumulation. Angiotensin II (Ang II) and inflammatory cytokines are increased in the heart following MI. We studied the involvement of mitogen-activated protein kinases (ERK1/2, JNKs, p38 kinase) and reactive oxygen species (ROS) in Ang II- and cytokine-induced OPN gene expression in adult rat cardiac fibroblasts. Ang II alone increased OPN mRNA (3.3 +/- 0.3-folds; P < 0.05; n = 7), while interleukin-1beta (IL-1beta), tumor necrosis factor (TNF-alpha), and interferon-gamma (IFN-gamma) had no effect. A combination of Ang II with IL-1beta or TNF-alpha, not IFN-gamma, increased OPN mRNA more than Ang II alone. Nitric oxide donor, S-nitrosoacetylpenicillamine (SNAP), alone or in combination with Ang II had no effect. Diphenylene iodonium (DPI), inhibitor of NAD(P)H oxidase, and tiron, superoxide scavenger, inhibited Ang II- and Ang II+ IL-1beta-stimulated increases in OPN mRNA. Ang II activated ERK1/2 within 5 min of treatment, not JNKs. IL-1beta activated ERK1/2 and JNKs within 15 min of treatment. A combination of Ang II and IL-1beta activated ERK1/2 within 5 min of treatment. None of these stimuli activated p38 kinase. DPI almost completely inhibited Ang II + IL-1beta-stimulated activation of ERK1/2, while partially inhibiting JNKs. PD98059, ERK1/2 pathway inhibitor, and SP600125, JNKs inhibitor, partially inhibited Ang II + IL-1beta-stimulated increases in OPN mRNA. A combination of PD98059 and SP600125 almost completely inhibited Ang II + IL-1beta-stimulated increases in OPN mRNA. Thus, Ang II alone increases OPN expression, while IL-1beta and TNF-alpha act synergistically with Ang II to increase OPN mRNA possibly via NO independent mechanisms. The synergistic increase in OPN mRNA involves ROS-mediated activation of ERK1/2 and JNKs, not P38 kinase, pathways in cardiac fibroblasts.
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PMID:ERK1/2 and JNKs, but not p38 kinase, are involved in reactive oxygen species-mediated induction of osteopontin gene expression by angiotensin II and interleukin-1beta in adult rat cardiac fibroblasts. 1475 45

Eosinophils constitutively produce and store matrix metalloproteinase-9 (MMP-9), a protease implicated in tissue remodeling observed in asthma. In this study, we examined the rapid release of stored MMP-9 from eosinophils following stimulation with either tumor necrosis factor-alpha (TNF-alpha or the bacterial product fMLP. TNF-alpha induced rapid and robust pro-MMP-9 release from eosinophils. MMP-9 could be detected in the cell-free supernatant as early as 15min after stimulation. Rapid MMP-9 release was similarly induced by fMLP. TNF-alpha stimulation activated the mitogen-activated protein (MAP) kinases p38 MAP kinase and extracellular signal-regulated kinase-2 (Erk-2) at times and concentrations similar to that observed for MMP-9 release. Using pharmacological inhibitors, we found that TNF-alpha-stimulated MMP-9 release was mediated by p38 MAP kinase, but not Erk-1/2. Signaling through p38 MAP kinase may represent a universal mechanism for MMP-9 release from eosinophils, as fMLP-induced MMP-9 release was also regulated by p38 MAP kinase.
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PMID:p38 MAP kinase regulates rapid matrix metalloproteinase-9 release from eosinophils. 1476 31

Results are presented which support the hypothesis that adequate steady-state levels of hydrogen peroxide (H2O2) are required to overcome the effects of high catalase and glutathione peroxidase (GPx) expression for p38 mitogen-activated protein (MAP) kinase activation and tumor necrosis factor (TNF)-alpha gene expression in human alveolar macrophages stimulated with asbestos. We found significant differences in the types and amounts of reactive oxygen species generated in human blood monocytes compared with human alveolar macrophages. This difference in reactive oxygen species production is related, in part, to the differences in antioxidant enzyme expression and activity. Most importantly, catalase and GPx activities were significantly increased in alveolar macrophages compared with blood monocytes. Asbestos activated the p38 MAP kinase and induced TNF-alpha gene expression only in blood monocytes. Increasing the steady-state levels of H2O2 by using polyethylene glycol superoxide dismutase, an antioxidant that crosses the cell membrane, or aminotriazole, an irreversible inhibitor of catalase, allowed the p38 MAP kinase to be activated in alveolar macrophages. In addition, asbestos-stimulated macrophages cultured with polyethylene glycol superoxide dismutase had a significant increase in gene expression mediated by the TNF-alpha promoter. These results demonstrate that high catalase and GPx activity in human alveolar macrophages limits the effectiveness of H2O2 to act as a mediator of inflammatory gene expression.
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PMID:High levels of catalase and glutathione peroxidase activity dampen H2O2 signaling in human alveolar macrophages. 1496 75

Fc gamma R clustering in macrophages activates signaling events that result in phagocytosis. Phagocytosis is accompanied by the generation harmful byproducts such as reactive oxygen radicals and production of inflammatory cytokines, which mandate that the phagocytic process be subject to a tight regulation. The molecular mechanisms involved in this regulation are not fully understood. In this study, we have examined the role of the inositol 3-phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in Fc gamma R-induced macrophage function. We demonstrate that in ex vivo murine peritoneal macrophages that are deficient in PTEN expression, Fc gamma R-induced Akt and extracellular signal-regulated kinase phosphorylation are enhanced. Notably, PTEN(-/-) macrophages showed constitutively high phosphorylation of Akt. However, PTEN did not seem to influence tyrosine phosphorylation events induced by Fc gamma R clustering. Furthermore, PTEN(-/-) macrophages displayed enhanced phagocytic ability. Likewise, Fc gamma R-induced production of TNF-alpha, IL-6, and IL-10 was significantly elevated in PTEN(-/-) macrophages. Surprisingly, LPS-induced TNF-alpha production was down-regulated in PTEN(-/-) macrophages. Analyzing the molecular events leading to PTEN influence on LPS/Toll-like receptor 4 (TLR4) signaling, we found that LPS-induced activation of mitogen-activated protein kinases is suppressed in PTEN(-/-) cells. Previous reports indicated that LPS-induced mitogen-activated protein kinase activation is down-regulated by phosphatidylinositol 3-kinase through the activation of Akt. Our observation that Akt activation is basally enhanced in PTEN(-/-) cells suggests that PTEN supports TLR4-induced inflammatory responses by suppressing the activation of Akt. Thus, we conclude that PTEN is a negative regulator of Fc gamma R signaling, but a positive regulator of TLR4 signaling. These findings are the first to demonstrate a role for PTEN in Fc gamma R- and TLR4-mediated macrophage inflammatory response.
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PMID:The inositol 3-phosphatase PTEN negatively regulates Fc gamma receptor signaling, but supports Toll-like receptor 4 signaling in murine peritoneal macrophages. 1506 63


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