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)

Circulating tumor necrosis factor alpha (TNF-alpha) has a profound stimulatory influence on mitogen-activated protein kinases that lead to nuclear factor kappa B (NF-kappaB) activity and transcription of the cyclooxygenase 2 (COX-2) gene in cells associated with the blood-brain barrier (BBB). This study investigated the hypothesis that nitric oxide (NO) acts as an endogenous modulator of TNF-induced NF-kappaB signaling and COX-2 transcription in the endothelium of the cerebral capillaries. To this end, rats were pretreated with the nonselective inhibitor of NO synthase (NOS) N(G)-nitro-L-arginine methyl ester (L-NAME) and killed 15, 45, and 90 minutes (min) after an i.v. injection of recombinant rat TNF-alpha. De novo expression of the inhibitory factor kappa B alpha (IkappaB alpha) was used as an index of NF-kappaB activity, whereas COX-2 mRNA induction was evaluated throughout the brain by in situ hybridization combined with immunohistochemistry. A single i.v. bolus of TNF caused a rapid expression of IkappaB alpha transcript first along large arterioles and small capillaries and thereafter within microglia across the brain parenchyma. The proinflammatory cytokine also provoked a strong transcriptional activation of the COX-2 gene that was quite specific to the cerebral endothelium as revealed by dual labeling using an antisera directed against the von Willebrand factor. Inhibition of NO synthesis did not by itself activate these proinflammatory molecules, but it enhanced the effects of circulating TNF-alpha in the BBB; the IkappaB alpha and COX-2 signal was significantly higher in microvascular-associated cells of animals that received both L-NAME and TNF-alpha treatments than those challenged with the proinflammatory cytokine alone. Rats treated with specific NOS inhibitors provided the evidence that these effects were mediated via the constitutive endothelial NOS (eNOS) and not the inducible form. These results indicate that eNOS-derived NO acts as an endogenous inhibitor of TNF-alpha-induced NF-kappaB activity and COX-2 transcription in the endothelium of the cerebral capillaries. This autoregulatory feedback of NO on these proinflammatory signal transduction events may be an essential element to prevent an exaggerated response that takes place in cells of the BBB during systemic immune challenges.
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PMID:Inhibitory action of nitric oxide on circulating tumor necrosis factor-induced NF-kappaB activity and COX-2 transcription in the endothelium of the brain capillaries. 1155 46

Nuclear factor kappaB (NF-kappaB) activation by NF-kappaB-inducing kinase (NIK)-IkappaB alpha kinase (IKK) pathway and mitogen-activated protein kinases (MAPKs) pathway are important in inflammation. We recently found that the tanshinone IIA, a diterpene isolated from Salvia miltiorrhiza (S. miltiorrhiza), reduced the production of pro-inflammatory mediators in RAW 264.7 cells stimulated with lipopolysaccharide (LPS). However, little is known about the inhibitory mechanisms of tanshinone IIA on the production of pro-inflammatory mediators. To investigate the inhibitory mechanism, we determined the inhibitory effects of tanshinone IIA on the activation of NF-kappaB and IkappaB alpha phosphorylation, and also examined phosphorylation of NIK and IKK as well as the activation of MAPKs such as p38 MAPK (p38), extracellular signal-regulated kinases 1/2 (ERK1/2), and c-Jun N-terminal kinase (JNK) in RAW 264.7 cells stimulated with LPS. Tanshinone IIA inhibited NF-kappaB-DNA complex, NF-kappaB binding activity, and the phosphorylation of IkappaB alpha in a dose dependent manner. Tanshinone IIA also inhibited the translocation of NF-kappaB from cytosol to nucleus. Moreover, the phosphorylation of NIK and IKK as well as the phosphorylation of p38, ERK1/2, and JNK in the LPS-stimulated RAW 264.7 cells were suppressed by the tanshinone IIA in a dose dependent manner. These results suggest that tanshinone IIA may inhibit LPS-induced IkappaB alpha degradation and NF-kappaB activation via suppression of the NIK-IKK pathway as well as the MAPKs (p38, ERK1/2, and JNK) pathway in RAW 264.7 cells and these properties may provide a potential mechanism that explains the anti-inflammatory activity of tanshinone IIA.
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PMID:Tanshinone IIA inhibits LPS-induced NF-kappaB activation in RAW 264.7 cells: possible involvement of the NIK-IKK, ERK1/2, p38 and JNK pathways. 1679 2

Inflammatory activation of glial cells is associated with neuronal injury in several degenerative movement disorders of the basal ganglia, including manganese neurotoxicity. Manganese (Mn) potentiates the effects of inflammatory cytokines on nuclear factor-kappaB (NF-kappaB)-dependent expression of nitric oxide synthase 2 (NOS2) in astrocytes, but the signaling mechanisms underlying this effect have remained elusive. It was postulated in the present studies that direct stimulation of cGMP synthesis and activation of mitogen-activated protein (MAP) kinase signaling pathways underlies the capacity of Mn to augment NF-kappaB-dependent gene expression in astrocytes. Exposure of primary cortical astrocytes to a low concentration of Mn (10 microM) potentiated expression of NOS2 mRNA and protein along with production of NO in response to interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha), which was prevented by overexpression of dominant negative IkappaB alpha. Mn also potentiated IFNgamma- and TNFalpha-induced phosphorylation of extracellular response kinase (ERK), p38, and JNK, as well as cytokine-induced activation of a fluorescent NF-kappaB reporter construct in transgenic astrocytes. Activation of ERK preceded that of NF-kappaB and was required for maximal activation of NO synthesis. Independently of IFNgamma/TNFalpha, Mn-stimulated synthesis of cGMP in astrocytes and inhibition of soluble guanylate cyclase (sGC) abolished the potentiating effect of Mn on MAP kinase phosphorylation, NF-kappaB activation, and production of NO. These data indicate that near-physiological concentrations of Mn potentiate cytokine-induced expression of NOS2 and production of NO in astrocytes via activation of sGC, which promotes ERK-dependent enhancement of NF-kappaB signaling.
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PMID:Manganese potentiates nuclear factor-kappaB-dependent expression of nitric oxide synthase 2 in astrocytes by activating soluble guanylate cyclase and extracellular responsive kinase signaling pathways. 1833 17

Plant polyphenols possess anti-oxidant and anti-inflammatory activities and are hence potential candidates for preventing cancer. The present study was aimed at evaluating the anti-inflammatory and anti-tumor promoting activity of oligonol, a formulation of catechin-type oligomers, in mouse skin stimulated with a proto-type tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Pretreatment of mouse skin with oligonol significantly inhibited TPA-induced expression of cyclooxygenase-2 (COX-2). Oligonol diminished nuclear translocation and DNA binding of nuclear factor-kappaB (NF-kappaB) via blockade of phosphorylation and subsequent degradation of IkappaB alpha in TPA-treated mouse skin. Moreover, oligonol suppressed TPA-induced DNA binding of CCAAT/enhancer-binding protein (C/EBP) in mouse skin. Oligonol pretreatment also attenuated the phosphorylation and/or catalytic activities of extracellular signal-regulated protein kinase-1/2 (ERK1/2) and p38 mitogen-activated protein (MAP) kinase. Moreover, p38 MAP kinase inhibitor SB203580, but not the MEK inhibitor U0126, negated TPA-induced DNA binding of C/EBP. In addition, oligonol reduced the incidence and the multiplicity of papillomas and squamous cell carcinomas in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and TPA-promoted mouse skin, and prolonged the survival of tumor-bearing mice. Pretreatment with oligonol diminished the levels of proliferating cell nuclear antigen and expression of COX-2 in papillomas and carcinomas, respectively, as compared to DMBA plus TPA treatment alone. Taken together, the above findings suggest that oligonol inhibits TPA-induced COX-2 expression by blocking the activation of NF-kappaB and C/EBP via modulation of MAP kinases and suppresses chemically induced mouse skin tumorigenesis.
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PMID:Inhibitory effects of oligonol on phorbol ester-induced tumor promotion and COX-2 expression in mouse skin: NF-kappaB and C/EBP as potential targets. 1884 48

We have shown earlier that mouse pancreatic acinar cells produce hydrogen sulfide (H(2)S) and play a role in the pathogenesis of acute pancreatitis. It is noteworthy that recent evidence indicates that H(2)S has anti-inflammatory effects. To date, the mechanism by which H(2)S directly reduces inflammation has not been elucidated. In the present study, we hypothesized that H(2)S inhibits the production of proinflammatory cytokines by activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. Pancreatic acinar cells were treated with the H(2)S donor, sodium hydrogen sulfide (NaHS) (5, 10, and 30 microM). To better understand the effect of H(2)S in inflammation, pancreatic acinar cells were stimulated with caerulein after the addition of NaHS (5, 10, and 30 microM). We observed that H(2)S at the 5 microM concentration down-regulates the activation of NF-kappaB and degradation of IkappaB alpha. However, H(2)S (5 microM) activates PI3K as reflected by AKT phosphorylation. We found that H(2)S-mediated activation of PI3K in caerulein-treated acinar cells correlated with the down-regulation of extracellular signal-regulated kinase 1/2 phosphorylation, whereas phosphorylation of p38 and c-Jun NH(2)-terminal kinase and mitogen-activated protein kinases was unchanged. The PI3K inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride] abolished the H(2)S-mediated activation of AKT and increases tumor necrosis factor alpha and interleukin 1beta levels in caerulein-treated acinar cells. These findings indicate that the phosphatidylinositol 3-kinase plays a negative role in NaHS-treated pancreatic acinar cells and suggest a role for H(2)S in the PI3K/AKT pathway in acute pancreatitis.
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PMID:Effect of hydrogen sulfide on the phosphatidylinositol 3-kinase-protein kinase B pathway and on caerulein-induced cytokine production in isolated mouse pancreatic acinar cells. 1925 18

Elevated blood and tissue CO(2), or hypercapnia, is common in severe lung disease. Patients with hypercapnia often develop lung infections and have an increased risk of death following pneumonia. To explore whether hypercapnia interferes with host defense, we studied the effects of elevated P(CO2) on macrophage innate immune responses. In differentiated human THP-1 macrophages and human and mouse alveolar macrophages stimulated with lipopolysaccharide (LPS) and other Toll-like receptor ligands, hypercapnia inhibited expression of tumor necrosis factor and interleukin (IL)-6, nuclear factor (NF)-kappaB-dependent cytokines critical for antimicrobial host defense. Inhibition of IL-6 expression by hypercapnia was concentration dependent, rapid, reversible, and independent of extracellular and intracellular acidosis. In contrast, hypercapnia did not down-regulate IL-10 or interferon-beta, which do not require NF-kappaB. Notably, hypercapnia did not affect LPS-induced degradation of IkappaB alpha, nuclear translocation of RelA/p65, or activation of mitogen-activated protein kinases, but it did block IL-6 promoter-driven luciferase activity in mouse RAW 264.7 macrophages. Elevated P(CO2) also decreased phagocytosis of opsonized polystyrene beads and heat-killed bacteria in THP-1 and human alveolar macrophages. By interfering with essential innate immune functions in the macrophage, hypercapnia may cause a previously unrecognized defect in resistance to pulmonary infection in patients with advanced lung disease.
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PMID:Elevated CO2 selectively inhibits interleukin-6 and tumor necrosis factor expression and decreases phagocytosis in the macrophage. 2018 40