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

Chemokines effect leukocyte chemotaxis and activation through their binding to specific G protein-coupled receptors. Although early steps in chemokine signal transduction pathways have been characterized, there is relatively limited information available at the transcription factor level. To that end, we have examined the binding activity on activation protein-1 (AP-1) and cyclic AMP responsive element (CRE) target sequences in human THP-1 myeloid cells after treatment with the beta-chemokine macrophage inflammatory protein (MIP-1alpha). MIP-1alpha induced both AP-1 and CRE activation. Although inhibition of protein kinase C blocked the AP-1 activity induced by this chemokine, there was no decrease in CRE activation in the presence of a protein kinase A inhibitor. Using kinase assays, it appeared that mitogen-activated protein kinase pathways were involved in CRE activation. In addition, HIV-1 infection of THP-1 cells resulted in constitutive activation of AP-1 and CRE elements but no further response to MIP-1alpha treatment. These results suggest that beta-chemokines act via protein kinase C-dependent pathways and mitogen-activated protein kinase pathways to modulate the host transcriptional response in myeloid cells, and that this response is altered by HIV infection.
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PMID:Beta-chemokine induction of activation protein-1 and cyclic AMP responsive element activation in human myeloid cells. 1133 Dec 50

The highly conserved region within the retroviral transmembrane envelope proteins has been implicated in a number of retrovirus-associated mechanisms of immunosuppression. CKS-17, a synthetic peptide representing the prototypic sequence of the immunosuppressive domain, has been found to suppress numerous immune functions, disregulate cytokines, and elevate intracellular cAMP. In this report we show that using a human monocytic cell line THP-1, CKS-17 activates mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase 1 and 2 (ERK1/2). Kinetic studies show that CKS-17 induces an acute increase of ERK1/2 activity followed by a rapid decrease and then a second sustained increase of ERK1/2. CKS-17 also activates MAP kinase/ERK kinase (MEK) with a similar induction pattern. Mutant THP-1 cells isolated in our laboratory, in which CKS-17 exclusively fails to activate cAMP, did not show the transient decrease of CKS-17-induced ERK1/2 phosphorylation. Pretreatment of THP-1 cells or mutant THP-1 cells with cAMP analog or forskolin followed by treatment with CKS-17 showed no activation of MEK or ERK1/2. These results indicate that CKS-17 activates the MEK/ERK cascade and that there is a cross-talk between CKS-17-mediated MEK/ERK cascade and cAMP in that the MEK/ERK cascade is negatively regulated by cAMP. These data present a novel molecular mechanism(s) by this highly conserved retroviral immunosuppressive component.
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PMID:A retroviral-derived immunosuppressive peptide activates mitogen-activated protein kinases. 1135 35

Tumor necrosis factor-alpha (TNF-alpha) is involved in insulin resistance. Since the fact that peroxisome proliferator-activated receptor gamma (PPARgamma) ligands inhibit the induction of TNF-alpha by phorbol ester, but not by lipopolysaccharide (LPS), suggests two pathways to induce TNF-alpha, we investigated the mechanisms of glycated human albumin (GHA)- or phorbol ester-induced TNF-alpha in THP-1 cells. GHA induced TNF-alpha release in differentiated THP-1 cells, while phorbol ester induced TNF-alpha release in undifferentiated cells but did not induce TNF-alpha in differentiated cells. Forskolin (adenylate cyclase activator) affected more the GHA-induced TNF-alpha release than the phorbol 12-myristate 13-acetate (PMA)-induced one in undifferentiated cells. Staurosporine [protein kinase-C (PK-C) inhibitor] and PD98059 [mitogen-activated protein kinase inhibitor (MAPK)] only partially inhibited GHA-induced TNF-alpha. Catalase completely inhibited GHA-induced TNF-alpha release; however, superoxide dismutase (SOD) had no effect. These results suggest at least two pathways to induce TNF-alpha (phorbol ester- and GHA-dependent ways) and that GHA-induced TNF-alpha release is through predominantly catalase-dependent way in differentiated THP-1 cells.
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PMID:Tumor necrosis factor-alpha is induced through phorbol ester--and glycated human albumin-dependent pathway in THP-1 cells. 1136 14

Advanced glycation end product (AGE) activation of the signal-transducing receptor for AGE (RAGE) has been linked to a proinflammatory phenotypic change within cells. However, the precise intracellular signaling pathways involved have not been elucidated. We demonstrate here that human serum albumin modified with N(epsilon)-(carboxymethyl)lysine (CML), a major AGE adduct that progressively accumulates with aging, diabetes, and renal failure, induced nuclear factor (NF)-kappaB-driven reporter gene expression in human monocytic THP-1 cells. The NF-kappaB response was blocked with a synthetic peptide corresponding to the putative ligand-binding domain of RAGE, with anti-RAGE antiserum, and by coexpression of truncated receptors lacking the intracellular domain. Signal transduction from RAGE to NF-kappaB involved the generation of reactive oxygen species, since reporter gene expression was blocked with the antioxidant N-acetyl-L-cysteine. CML-modified albumin produced rapid transient activation of tyrosine phosphorylation, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinase (MAPK), but not c-Jun NH(2)-terminal kinase. RAGE-mediated NF-kappaB activation was suppressed by the selective p38 MAPK inhibitor SB203580 and by coexpression of a kinase-dead p38 dominant-negative mutant. Activation of NF-kappaB by CML-modified albumin increased secretion of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, and monocyte chemoattractant protein-1) severalfold, and inhibition of p38 MAPK blocked these increases. These results indicate that p38 MAPK activation mediates RAGE-induced NF-kappaB-dependent secretion of proinflammatory cytokines and suggest that accelerated inflammation may be a consequence of cellular activation induced by this receptor.
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PMID:Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. 1137 53

Hyperinsulinemia has recently been reported as a risk factor for atherosclerotic diseases such as coronary heart disease; however, the effect of insulin on the development of atherosclerosis is not well understood. Here we have investigated the direct effect of insulin on macrophages, which are known to be important in the atherosclerotic process. We treated THP-1 macrophages with insulin (10(-7) m) and examined the gene expression using nucleic acid array systems. The results of array analysis showed that insulin stimulated gene expression of tumor necrosis factor-alpha (TNF-alpha) the most among all genes in the analysis. In addition, insulin administration to macrophages enhanced both mRNA expression and protein secretion of TNF-alpha in a dose-dependent manner. To determine the signaling pathway involved in this TNF-alpha response to insulin, we pretreated the cells with three distinct protein kinase inhibitors: wortmannin, PD98059, and SB203580. Only PD98059, which inhibits extracellular signal-regulated kinases, suppressed insulin-induced production of TNF-alpha mRNA and protein in THP-1 macrophages. These observations indicate that insulin stimulates TNF-alpha production in macrophages by regulating the expression of TNF-alpha mRNA and that the extracellular signal-regulated kinase signaling pathway may have a critical role in stimulating the production of TNF-alpha in response to insulin in macrophages.
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PMID:Insulin up-regulates tumor necrosis factor-alpha production in macrophages through an extracellular-regulated kinase-dependent pathway. 1144 8

Apoptotic regulation of monocytes/macrophages appears to be closely associated with chronic inflammatory reactions. Since it was demonstrated earlier that certain bacterial cell components are involved in apoptotic regulation of these cells, in the present study, we investigated whether the bacterial fimbria, an important cell structure involved in bacterial adherence to host cells, regulates apoptosis of human monocytic THP-1 cells induced under growth factor deprivation. To investigate this point, we used fimbriae of Porphyromonas gingivalis, a pathogen causing periodontal disease, which is a chronic inflammatory disease. The fimbriae inhibited apoptosis of the cells under growth factor deprivation. This inhibitory action of the fimbriae was completely neutralized by anti-fimbrial antibody. The fimbriae stimulated activation of extracellular signal-regulated kinase (ERK) and expression of cyclin-dependent kinase inhibitor p21 Cip/WAF1 (p21) in the cells. The stimulatory effect of the fimbriae on the expression of the p21 protein was inhibited by treatment with PD98059, a specific inhibitor of ERK. The cell apoptosis was inhibited by treatment with Ac-DEVD-CHO, an inhibitor of caspase-3. The fimbriae inhibited the serum withdrawal-induced cleavage of the caspase-3 proform and poly(ADP-ribose) polymerase, one of the caspase-3 substrates. Furthermore, PD98059 and antisense p21 oligonucleotide blocked the fimbrial inhibition of apoptosis and caspase-3 activation of the cells induced by serum withdrawal. These results show that the bacterial fimbriae inhibited apoptosis of THP-1 cells induced under growth factor deprivation via ERK-dependent expression of p21. The present study suggests that bacterial fimbriae act as potent regulators of chronic inflammatory disease, e.g., periodontal disease, through blocking apoptosis of monocytes/macrophages.
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PMID:Porphyromonas gingivalis fimbriae inhibit caspase-3-mediated apoptosis of monocytic THP-1 cells under growth factor deprivation via extracellular signal-regulated kinase-dependent expression of p21 Cip/WAF1. 1144 72

Activator protein 1 (AP-1) binds to the promoters of many genes involved in immune and inflammatory responses. We have previously shown that the p38 mitogen-activated protein (MAP) kinase regulates NF-kappa B-dependent gene expression by modulating the phosphorylation and subsequent activation of TATA-binding protein (TBP). In this study, we asked whether the p38 MAP kinase regulated the transcriptional activity of AP-1. We found that phorbol 12-myristate 13-acetate (PMA) was unable to drive the AP-1-dependent reporter gene in THP-1 cells. PMA activated both the extracellular signal-regulated kinase and c-Jun NH(2)-terminal kinase MAP kinases, but it did not activate the p38 MAP kinase. We found that cells expressing MAP kinase kinase 6(Glu), which is the upstream kinase that activates the p38 MAP kinase, had significantly increased AP-1-dependent gene expression alone and when stimulated with PMA. These cells also had increased phosphorylation of native c-Jun, suggesting that both c-Jun NH(2)-terminal kinase and p38 MAP kinases phosphorylate c-Jun. More importantly, expression of a constitutive active MAP kinase kinase 6(Glu) resulted in the phosphorylation of a His-TBP fusion protein and increased direct interaction of TBP with c-Jun. These findings suggest that in macrophages, the p38 MAP kinase regulates AP-1-driven transcription by modulating the activation of TBP.
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PMID:The absence of activator protein 1-dependent gene expression in THP-1 macrophages stimulated with phorbol esters is due to lack of p38 mitogen-activated protein kinase activation. 1145 54

Various inhibitors of protein kinases regulate the growth and differentiation of human leukemic cell lines. The pyridinyl imidazole inhibitor SB203580 has been widely used to elucidate the role of p38 kinase in a wide array of biological systems. In the present investigation, we found that SB203580 effectively induced the granulocytic differentiation of human promyelocytic HL-60 cells. In addition to morphological differentiation, it also induced NBT-reduction, lysozyme activity and growth-inhibition. It also induced the differentiation of human myeloid leukemia HT93 and ML-1 cells, but not of other cell lines, such as NB4, U937, THP-1, K562 and HEL. This differentiation was not associated with the inhibition of p38 kinase activity, but was closely associated with the activation of extracellular signal-regulated kinase. These results demonstrate a new activity for this drug.
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PMID:Pyridinyl imidazole inhibitor SB203580 activates p44/42 mitogen-activated protein kinase and induces the differentiation of human myeloid leukemia cells. 1148 75

We show that radicicol, an anti-fungal agent, inhibits interleukin-8 (IL-8) production by the human monocyte line THP-1 in response to phorbol-12-myristate-13-acetate/lipopolysaccharide (PMA/LPS). IL-8 is a potent chemokine and needs for an optimal immune response--such as inflammation by activation of neutrophils. The decrease in PMA/LPS-induced IL-8 mRNA expression was demonstrated by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Since the promoter in IL-8 gene contains binding motifs for NF-KB, AP-1. and NF-IL6, which appear to be important in IL-8 induction, the effects of radicicol on the activation of these transcription factors were examined. Treatment of radicicol to THP-1 cells produced a strong inhibition of NF-KB and AP-1, while NF-IL6 was not significantly affected by radicicol. Western blot analysis showed that radicicol inhibited the phosphorylation and phosphotransferase activities of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38. PD98059 and SB203580, known as a specific inhibitor of MEKI and p38 kinase, respectively, inhibited IL-8 gene expression showing that both of the kinase pathways are involved in IL-8 regulation in human monocytes. Collectively, this series of experiments indicates that radicicol inhibits IL-8 gene expression by blocking ERK1/2 and p38 signaling.
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PMID:Suppression of IL-8 gene expression by radicicol is mediated through the inhibition of ERK1/2 and p38 signaling and negative regulation of NF-kappaB and AP-1. 1156 79

The molecular events that transduce signals from Fc receptors to the various cellular responses are still poorly defined. We have investigated the role of phosphatidylinositol 3-kinase (PI 3-K) and extracellular signal-regulated kinase (ERK) in gene activation and phagocytosis in monocytes. In the THP-1 monocytic cell line, cross-linking of Fc receptors by immune complexes results in activation of the transcription factor NF-kappaB, via activation of ERK. Activation of both ERK and NF-kappaB was blocked by wortmannin and LY294002, specific inhibitors of PI 3-K. Wortmannin also inhibited the Fc receptor-mediated increase in the cytosolic calcium concentration, but it did not block immunoglobulin G (IgG)-mediated phagocytosis. In addition, the ERK inhibitor PD98059 did not block phagocytosis of IgG-coated erythrocytes. Both the increase in the cytosolic calcium concentration and phagocytosis depend on an active actin cytoskeleton, as indicated by the total lack of both responses after treatment with cytochalasin B. In contrast, cytochalasin B did not affect Fc receptor-mediated activation of NF-kappaB. These results identify PI 3-K and ERK as important signaling molecules in the Fc receptor signal transduction pathway of monocytes, which leads to the nucleus for gene activation. These results also suggest that, in contrast to other cell types, unstimulated monocytes do not require PI 3-K and ERK for phagocytosis.
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PMID:Phosphatidylinositol 3-kinase and ERK are required for NF-kappaB activation but not for phagocytosis. 1159 Feb 3


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