Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vitamin E-succinate (VES) induced monocvtic differentiation of HL-60 human leukemia cells. Treatment with VES increased the nitroblue tetrazolium reduction activity, and the expression of monocyte specific cell surface antigen, CD14 and c-fms. During the monocytic differentiation of HL-60 cells that were induced by VES, the phosphorylation of extracellular signal-regulated protein kinase (ERK) was increased by 12 h and then gradually decreased to a level that was similar to that of the control. However, the phosphorylation levels of p38 and JNK, as well as the expression levels of ERK, p38, and JNK, were unchanged by the VES treatment. Treatment with VES also induced hypophosphorylation of the retinoblastoma protein and an increase of the p21WAF1 protein level. VES-induced ERK phosphorylation was abolished by the ERK inhibitor, PD98059, which resulted in a remarkable prevention of VES-induced monocytic differentiation. Inhibition of the ERK activity by PD98059 also diminished the VES-induced p21WAF1 protein expression, but did not change the phosphorylation state of the retinoblastoma protein. Collectively, these data suggest that the ERK signaling pathway mediates the up-regulation of the p21xWAF1 expression that is induced by VES, which is required for monocytic differentiation of HL 60 cells.
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PMID:Expression of p21WAF1 is dependent on the activation of ERK during vitamin E-succinate-induced monocytic differentiation. 1191 63

Lipopolysaccharide (LPS) has a profound effect on cardiac performance through a collapse of the vasculature. In this study, we determined whether LPS has a direct effect on the cardiac myocytes by examining the expression of the BNP gene in cultured neonatal rat cardiac myocytes. Northern blot analysis showed that LPS induces the expression of the BNP gene. Time-course experiments revealed that BNP mRNA levels were increased 1 h after LPS stimulation. Enhanced induction of BNP was observed 3 h after stimulation when expression of CD14, a specific receptor for LPS, was markedly induced. LPS-mediated BNP expression was completely inhibited by the pretreatment of SB203580, a specific inhibitor for p38 MAPK as well as by genistein, a broad range tyrosine kinase inhibitor. In accordance with these results, LPS increases phosphorylation of p38 mitogen-activated protein kinase (MAPK). Transient transfection assays revealed that low dose (1 ng/ml) of LPS induces the luciferase activity derived from the construct containing the BNP promoter spanning from -1000 and +80 in front of the luciferase gene. Cotransfection of the expression vectors for constitutive active forms of Rac1, MKK3 and p38 MAPK significantly increased BNP promoter activity. Mutation of the GATA sequence located at -95 and -84 abolished such an induction of BNP promoter activity. Overexpression of CD14 enhanced the LPS's effect on BNP promoter. These results indicate that LPS induces the BNP gene expression through a pathway involving CD14, Rac1, p38 MAPK and GATA elements. In addition to the induction of BNP expression by hemodynamic overload, our data suggest that elevated levels of BNP under the endotoxemic condition is partly mediated through the increased expression of CD14, which lies upstream of the Rac1-p38 MAPK pathway.
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PMID:Transcriptional activation of the BNP gene by lipopolysaccharide is mediated through GATA elements in neonatal rat cardiac myocytes. 1205 52

The liver is an important site of host-microbe interaction. Although hepatocytes have been reported to be responsive to lipopolysaccharide (LPS), the global gene expression changes by LPS and mechanism(s) by which LPS stimulates cultured hepatocytes remain uncertain. Cultures of primary mouse hepatocytes were incubated with LPS to assess its effects on the global gene expression, hepatic transcription factors, and mitogen-activated protein (MAP) kinase activation. DNA microarray analysis indicated that LPS modulates the selective expression of more than 80 genes and expressed sequence tags. We have shown previously that hepatocytes express CD14, which is required both for uptake and responsiveness to LPS. In other cells, responsiveness to microbial products requires expression of Toll-like receptors (TLR) and their associated accessory molecules. Hepatocytes expressed TLR1 through TLR9 as well as MyD88 and MD-2 transcripts, as shown by reverse transcriptase PCR analysis, indicating that hepatocytes express all known microbe recognition molecules. The MAP kinase extracellular signal-regulated kinase 1/2 was phosphorylated in response to LPS in mouse hepatocytes, and the levels of phosphorylation were lower in hepatocytes from TLR4-null mice. NF-kappa B activation was reduced in TLR4-mutant or -null hepatocytes compared to control hepatocytes, and this defect was partially restored by adenoviral transduction of mouse TLR4. Thus, hepatocytes respond to nanogram concentrations of LPS through a TLR4 response pathway.
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PMID:Role of toll-like receptors in changes in gene expression and NF-kappa B activation in mouse hepatocytes stimulated with lipopolysaccharide. 1206 83

Periodontal disease is the major cause of adult tooth loss and is commonly characterized by a chronic inflammation caused by infection of oral bacteria. Porphyromonas gingivalis (P. gingivalis) is one of the suspected periodontopathic bacteria and is frequently isolated from the periodontal pockets of patients with chronic periodontal disease. The lipopolysaccharide (LPS) of P. gingivalis is a key factor in the development of periodontitis. Gingival fibroblasts, which are the major constituents of gingival connective tissue, may directly interact with bacteria and bacterial products, including LPS, in periodontitis lesions. It is suggested that gingival fibroblasts play an important role in the host responses to LPS in periodontal disease. P. gingivalis LPS enhances the production of inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor alpha (TNF-alpha) in gingival fibroblasts. However, the receptor that binds with P. gingivalis LPS on gingival fibroblasts remained unknown for many years. Recently, it was demonstrated that P. gingivalis LPS binds to gingival fibroblasts. It was also found that gingival fibroblasts express CD14, Toll-like receptor 4 (TLR4), and myeloid differentiation primary response gene 88 (MyD88). P. gingivalis LPS treatment of gingival fibroblasts activates several intracellular proteins, including protein tyrosine kinases, and up-regulates the expression of monocyte chemoattractant protein-1 (MCP-1), extracellular signal-regulated kinase 1 (ERK1), and signal-regulated kinase 2 (ERK2), IL-1 receptor-associated kinase (IRAK), nuclear factor-kappaB (NF-kappaB), and activating protein-1 (AP-1). These results suggest that the binding of P. gingivalis LPS to CD14 and TLR4 on gingival fibroblasts activates various second-messenger systems. In this article, we review recent findings on the signaling pathways induced by the binding of P. gingivalis LPS to CD14 and Toll-like receptors (TLRs) in gingival fibroblasts.
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PMID:Porphyromonas gingivalis lipopolysaccharide signaling in gingival fibroblasts-CD14 and Toll-like receptors. 1209 56

Tolerance to bacterial cell wall components including lipopolysaccharide (LPS) may represent an essential regulatory mechanism during bacterial infection. Two members of the Toll-like receptor (TLR) family, TLR2 and TLR4, recognize the specific pattern of bacterial cell wall components. TLR4 has been found to be responsible for LPS tolerance. However, the role of TLR2 in bacterial lipoprotein (BLP) tolerance and LPS tolerance is unclear. Pretreatment of human THP-1 monocytic cells with a synthetic bacterial lipopeptide induced tolerance to a second BLP challenge with diminished tumor necrosis factor-alpha and interleukin-6 production, termed BLP tolerance. Furthermore, BLP-tolerized THP-1 cells no longer responded to LPS stimulation, indicating a cross-tolerance to LPS. Induction of BLP tolerance was CD14-independent, as THP-1 cells that lack membrane-bound CD14 developed tolerance both in serum-free conditions and in the presence of a specific CD14 blocking monoclonal antibody (MEM-18). Pre-exposure of THP-1 cells to BLP suppressed mitogen-activated protein kinase phosphorylation and nuclear factor-kappaB activation in response to subsequent BLP and LPS stimulation, which is comparable with that found in LPS-tolerized cells, indicating that BLP tolerance and LPS tolerance may share similar intracellular pathways. However, BLP strongly enhanced TLR2 expression in non-tolerized THP-1 cells, whereas LPS stimulation had no effect. Furthermore, a specific TLR2 blocking monoclonal antibody (2392) attenuated BLP-induced, but not LPS-induced, tumor necrosis factor-alpha and interleukin-6 production, indicating BLP rather than LPS as a ligand for TLR2 engagement and activation. More importantly, pretreatment of THP-1 cells with BLP strongly inhibited TLR2 activation in response to subsequent BLP stimulation. In contrast, LPS tolerance did not prevent BLP-induced TLR2 overexpression. These results demonstrate that BLP tolerance develops through down-regulation of TLR2 expression.
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PMID:Induction of bacterial lipoprotein tolerance is associated with suppression of toll-like receptor 2 expression. 1213 36

Gastric infection, as well as inflammation, caused by Helicobacter pylori, activates the production of cytokines and chemokines by mononuclear cells; interleukin-8 (IL-8) is one of the major inflammatory chemokines. Since H. pylori does not invade mucosal tissue, we observed the effect of the water extract of H. pylori (HPE), containing shed factors, on the production of IL-8 by human peripheral blood monocytes and the human monocyte cell line THP-1. HPE-treatment induced activation of the mitogen-activated protein kinases (MAPKs) ERK (extracellular signal-regulated kinase), p38 and JNK (c-Jun N-terminal kinase), an effect which was not dependent on the presence of the cag pathogenicity island. p38 MAPK activation was sustained. The specific inhibitors, U0126 (for ERK1/2 signalling) and SB203580 (for p38 MAPK signalling), both abrogated IL-8 secretion from HPE-treated THP-1. Dominant-negative mutants of the upstream kinases MEK1 (MAPK/ERK kinase 1), MKK (MAPK kinase) 6 and MKK7 also inhibited IL-8 secretion, pointing to a role of all three MAPKs in HPE-mediated IL-8 release. The inhibitory effects of polymyxin B and anti-CD14 antibody suggested that the effect of HPE on MAPKs was mediated by H. pylori lipopolysaccharide (LPS). By analysis of IL-8-promoter-driven luciferase gene expression, we observed that the effects of HPE-induced nuclear factor-kappaB (NF-kappaB) activation and MAPK signalling were mediated at the level of the IL-8 promoter. While ERK1/2 activation could be linked to enhanced DNA binding of activator protein-1 (AP-1), p38 MAPK signalling did not affect AP-1 DNA binding. Taken together, these results provide the first evidence that LPS from H. pylori stimulates IL-8 release from cells of the monocytic lineage through activation of NF-kappaB and signalling along MAPK cascades. The stimulation of MAPK signalling in macrophages by LPS of H. pylori amplifies the inflammatory response associated with gastric H. pylori infection and needs to be taken into consideration when developing therapeutics based on these signalling pathways.
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PMID:Mitogen-activated protein kinases and nuclear factor-kappaB regulate Helicobacter pylori-mediated interleukin-8 release from macrophages. 1215 Jul 10

Pyelonephritis, in which renal tubular epithelial cells are directly exposed to bacterial component, is a major predisposing cause of renal insufficiency. Although previous studies have suggested C-C chemokines are involved in the pathogenesis, the exact source and mechanisms of the chemokine secretion remain ambiguous. In this study, we evaluated the involvement of Toll-like receptors (TLRs) in C-C chemokine production by mouse primary renal tubular epithelial cells (MTECs). MTECs constitutively expressed mRNA for TLR1, 2, 3, 4, and 6, but not for TLR5 or 9. MTECs also expressed MD-2, CD14, myeloid differentiation factor 88, and Toll receptor-IL-1R domain-containing adapter protein/myeloid differentiation factor 88-adapter-like. Synthetic lipid A and lipoprotein induced monocyte chemoattractant protein 1 (MCP-1) and RANTES production in MTECs, which strictly depend on TLR4 and TLR2, respectively. In contrast, MTECs were refractory to CpG-oligodeoxynucleotide in chemokine production, consistently with the absence of TLR9. LPS-mediated MCP-1 and RANTES production in MTECs was abolished by NF-kappaB inhibition, but unaffected by extracellular signal-regulated kinase inhibition. In LPS-stimulated MTECs, inhibition of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase significantly decreased RANTES, but did not affect MCP-1 mRNA induction. Thus, MTECs have a distinct expression pattern of TLR and secrete C-C chemokines in response to direct stimulation with a set of bacterial components.
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PMID:Roles of toll-like receptors in C-C chemokine production by renal tubular epithelial cells. 1216 29

Yeast expressed Hepatitis B surface antigen (rHBsAg) binds to monocytes through interaction with the LPS binding protein (LBP) and the LPS receptor CD14. Charged phospholipids of rHBsAg determine the interaction with these proteins. Although attachment of rHBsAg resembles the pro-inflammatory binding of LPS to CD14, rHBsAg does not activate monocytes and even reduces the expression of pro-inflammatory cytokines by LPS-stimulated monocytes. It is reported here that addition of rHBsAg to LPS-stimulated PBMC often results in increased secretion of IL-10, suggesting a similarity between the interaction of monocytes with apoptotic cells and rHBsAg. Using THP-1 cells, it is shown that IL-10 is not necessary to reduce TNFalpha protein levels. Addition of rHBsAg to LPS-stimulated cells reduces TNFalpha mRNA levels, but does not affect phosphorylation of p65 NF-kappaB and p38 MAP kinase. Instead, a reduced phosphorylation of ERK-1/2 and JNK-1/2 MAP kinases is observed.
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PMID:Recombinant HBsAg, an apoptotic-like lipoprotein, interferes with the LPS-induced activation of ERK-1/2 and JNK-1/2 in monocytes. 1227 Jan 19

It is well known that elevated intracellular cAMP induces growth arrest and the differentiation of HL-60 cells to neutrophil-like cells. The present study was designed to assess the regulation of the extracellular signal-regulated kinase (ERK) pathway by cAMP and its association with differentiation in HL-60 cells. We found that 8-bromoadenosine-3',5'-cyclic-monophosphate (8Br-cAMP)-induced the activation of ERK and mitogen-activated protein kinase (MEK), but inhibited B-Raf kinase via a protein kinase A (PKA)-mediated mechanism. Prolonged exposure to 8Br-cAMP increased the phorbol 12-myristate 13-acetate (TPA)-stimulated superoxide generation and CD14 expression that characterize the differentiation phenotype, which was blocked by MEK-1 inhibitor. These data suggest that cAMP-induced ERK activation is essential for the differentiation of HL-60 cells, independently of B-Raf.
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PMID:Cyclic AMP induces activation of extracellular signal-regulated kinases in HL-60 cells: role in cAMP-induced differentiation. 1247 52

The pyridinyl imidazole p38 kinase inhibitor, SB203580, was initially used to block inflammatory cytokine synthesis. Here we report that SB203580 by itself could induce human promyeloid leukemic HL-60 cells to differentiate mainly along the granulocytic lineage, as evidenced by cellular morphological changes, and the concurrent expression of cell surface markers CD11b and CD14. This differentiation induction was time and dose dependent. After 12 h exposure to 10 microM SB203580, 12.5% of the cells became CD11b as compared to only 2.6% in untreated control cells. By 96 h, CD11b cells increased to 72.3%, and among them, 26% were CD14. Morphologically, the cells were smaller in size with lower nuclear/cytoplasmic ratio. The nucleus was indented and nucleoli markedly reduced. However, 10 microM SB203580 had little effect on HL-60 cell growth and survival during the first 72 h, but by 96 h the percentage of cells in G1 phase was markedly increased. These effects of SB203580 were not attributable to its inhibition of p38 kinase activity. Instead, the essential kinases in the extracellular signal-regulated kinase (ERK) pathway such as phospho-Raf-1, phospho-MEK1/2, phospho-ERK1/2 and phospho-p90RSK were all elevated dramatically shortly after cells were exposed to SB203580 and lasted for 24 h before declining. Pre-incubation of cells with 20 microM of PD98059 1 h before addition of SB203580 could completely block the expression of differentiation markers. Our results suggest that SB203580-induced differentiation in HL-60 cells was mediated by activation of MEK/ERK signaling. In conclusion, our data have shown that SB203580 possessed biological activities other than inhibition of p38 and these activities could make it a potential candidate as an inducing agent for cell differentiation in the therapeutic treatment of leukemia.
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PMID:Induction of HL-60 cell differentiation by the p38 mitogen-activated protein kinase inhibitor SB203580 is mediated through the extracellular signal-regulated kinase signaling pathway. 1254 56


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