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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Levo-tetrahydropalmatine (l-THP) is an alkaloid purified from the Chinese herb corydalis and stephania and is contained in many traditional Chinese herbal preparations. Our previous studies demonstrated the ability of l-THP to inhibit locomotor stimulation and physical dependence induced by oxycodone in mice and rats. The present study was designed to evaluate effects of l-THP on reward of oxycodone using conditioned place preference assay. Oxycodone (0.32-5.0 mg/kg) induced the development of conditioned place preference in rats. Furthermore, oxycodone (2.5 mg/kg) induced the increased phosphorylation of CREB and ERK in nucleus accumbens and hippocampus, but not in prefrontal cortex. l-THP (6.25-18.50 mg/kg) per se was not able to induce conditioned place preference or conditioned place aversion. l-THP co-administered with oxycodone during the conditioning sessions partly abolished the development of oxycodone-induced conditioned place preference in rats. Furthermore, l-THP inhibited the increased phosphorylation of ERK and CREB in nucleus accumbens and hippocampus of rats. All these results suggest that l-THP can inhibit oxycodone-induced psychological dependence by affecting phosphorylation of CREB and ERK in nucleus accumbens and hippocampus of rats. Together, the present data, combined with previous finding, support the potential use of l-THP for treatment of oxycodone addiction.
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PMID:Levo-tetrahydropalmatine attenuates oxycodone-induced conditioned place preference in rats. 1907 Nov 7

The decidual microenvironment is characterized by a unique population of leukocytes composed primarily of CD56(bright) NK cells and macrophages. The latter are situated near trophoblast cells at the fetal-maternal interface and there is evidence that trophoblast cells are capable of recruiting macrophages to this site. This study sought to determine the role of tumour necrosis factor alpha (TNF) in the trophoblast-mediated recruitment of monocyte-derived macrophages to the fetal-maternal interface. The human first trimester extravillous trophoblast cell line HTR-8/SVneo was shown to express TNFR1 and to secrete the monocyte-attracting chemokines CCL2 and CCL5 after exposure to TNF in a dose-dependent manner. TNF-mediated stimulation of CCL2 secretion was completely inhibited by incubating the trophoblast cells with the p38-MAPK inhibitor SB203580, whereas CCL5 secretion was inhibited by treating the trophoblast cells with inhibitors specific for JNK (SP600125) and ERK kinase (U0126). Media conditioned by TNF-treated trophoblast cells significantly enhanced the ability of the monocyte cell line THP-1 to invade through Matrigel, and this effect was inhibited using antibodies specific for CCL2 and CCL5. These results support a role for TNF at the fetal-maternal interface as a regulator of macrophage recruitment by trophoblast cells.
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PMID:Tumour necrosis factor alpha stimulates the production of monocyte chemoattractants by extravillous trophoblast cells via differential activation of MAPK pathways. 1920 63

To determine whether macrophage differentiation involves increased uptake of vitamin C, or ascorbic acid, we assessed the expression and function of its transporter SVCT2 during phorbol ester-induced differentiation of human-derived THP-1 monocytes. Induction of THP-1 monocyte differentiation by phorbol 12-myristate 13-acetate (PMA) markedly increased SVCT2 mRNA, protein, and function. When ascorbate was present during PMA-induced differentiation, the increase in SVCT2 protein expression was inhibited, but differentiation was enhanced. PMA-induced SVCT2 protein expression was blocked by inhibitors of protein kinase C (PKC), with most of the affect due to the PKCbetaI and betaII isoforms. Activation of MEK/ERK was sustained up to 48 h after PMA treatment, and the inhibitors completely blocked PMA-stimulated SVCT2 protein expression, indicating an exclusive role for the classical MAP kinase pathway. However, inhibitors of NF-kappaB activation, NADPH oxidase inhibitors, and several antioxidants also partially prevented SVCT2 induction, suggesting diverse distal routes for control of SVCT2 transcription. Both known promoters for the SVCT2 were involved in these effects. In conclusion, PMA-induced monocyte-macrophage differentiation is enhanced by ascorbate and associated with increased expression and function of the SVCT2 protein through a pathway involving sustained activation of PKCbetaI/II, MAP kinase, NADPH oxidase, and NF-kappaB.
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PMID:Macrophage differentiation increases expression of the ascorbate transporter (SVCT2). 1923 38

Interferon (IFN)-gamma-induced protein 10 (IP-10/CXCL10), a CXC chemokine, has been documented in several inflammatory and autoimmune disorders including atopic dermatitis and bronchial asthma. Although CXCL10 could be induced by IFN-gamma depending on cell type, the mechanisms regulating CXCL10 production following treatment with combination of IFN-gamma and TNF-alpha have not been adequately elucidated in human monocytes. In this study, we showed that TNF-alpha had more potential than IFN-gamma to induce CXCL10 production in THP-1 monocytes. Furthermore, IFN-gamma synergistically enhanced the production of CXCL10 in parallel with the activation of NF-kappaB in TNF-alpha-stimulated THP-1 cells. Blockage of STAT1 or NF-kappaB suppressed CXCL10 production. JAKs inhibitors suppressed IFN-gamma plus TNF-alpha-induced production of CXCL10 in parallel with activation of STAT1 and NF-kappaB, while ERK inhibitor suppressed production of CXCL10 as well as activation of NF-kappaB, but not that of STAT1. IFN-gamma-induced phosphorylation of JAK1 and JAK2, whereas TNF-alpha induced phosphorylation of ERK1/2. Interestingly, IFN-gamma alone had no effect on phosphorylation and degradation of IkappaB-alpha, whereas it significantly promoted TNF-alpha-induced phosphorylation and degradation of IkappaB-alpha. These results suggest that TNF-alpha induces CXCL10 production by activating NF-kappaB through ERK and that IFN-gamma induces CXCL10 production by increasing the activation of STAT1 through JAKs pathways. Of note, TNF-alpha-induced NF-kappaB may be the primary pathway contributing to CXCL10 production in THP-1 cells. IFN-gamma potentiates TNF-alpha-induced CXCL10 production in THP-1 cells by increasing the activation of STAT1 and NF-kappaB through JAK1 and JAK2.
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PMID:Essential involvement of cross-talk between IFN-gamma and TNF-alpha in CXCL10 production in human THP-1 monocytes. 1947 12

The purpose of present study was to explore the possibility of Tec kinase as a mediator for IL-8 transcription in monocytes stimulated with LPS. Plasmids of mouse Tec kinase IV or Tec kinase IV with inactivating point mutations generated with QuikChange site-directed mutagenesis were co-transfected with IL-8 promoter driven luciferase construct into RAW264.7 cells, then luciferase activity was measured with a luminometer. The results shown Tec kinase could significantly enhance IL-8 transcription. Furthermore, point inactivating mutation in SH2, PH or PTK domain almost completely abolish the effects of Tec kinase on the transcription of IL-8. In the transfection experiment, PD98059, a MEK1 inhibitor, decreased the transcription of IL-8 in a dose dependent pattern. When siRNA for Tec kinase was transfected into THP-1 cells, it could efficiently block the production of IL-8 from THP-1 cells (p < 0.01) stimulated with LPS. In conclusion, Tec kinase may mediate the transcription of IL-8 in monocyte stimulated with LPS.
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PMID:Tec kinase mediating IL-8 transcription in monocytes stimulated with LPS. 1950 16

It is recognized that respiratory sensitization is a hazard of high concern. Despite international regulatory requirements there is no established protocol for the identification of chemical respiratory sensitizers. New tests should be based on mechanistic understanding and should be preferentially restricted to in vitro assays. The major goal of this study was to investigate the genetic response of human THP-1 macrophages after contact with respiratory (non-)sensitizers, and to identify genes that are able to discriminate between both groups. THP-1 macrophages were exposed during different time points to 3 respiratory sensitizers, 2 irritants, and 1 skin sensitizer. Gene expression changes were evaluated using Agilent Whole Human Genome arrays. Fisher Linear Discriminant Analysis was used to obtain a ranking of genes that reflects their potential to discriminate between respiratory (non-)sensitizing chemicals. Among the 20 most discriminating genes which were categorized into molecular and biological Gene Ontology (GO) terms, EIF4E, PDGFRB, SEMA7A, and ZFP36L2 could be associated with respiratory sensitization. When categorizing the top-1000 genes into biological GO terms, 24 genes were associated with immune function. Using a pathway analysis tool, platelet-derived growth factor signaling was observed to be activated in THP-1 macrophages in the context of respiratory sensitization.
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PMID:Gene profiles of THP-1 macrophages after in vitro exposure to respiratory (non-)sensitizing chemicals: identification of discriminating genetic markers and pathway analysis. 1952 80

Macrolide antibiotics are known to have a variety of immunomodulatory effects in addition to antimicrobial activity, but the mechanisms of immunomodulation are still unclear. We investigated in vitro the effect of azithromycin on tumor necrosis factor alpha (TNF-alpha) production in lipopolysaccharide (LPS)-stimulated THP-1 cells, a human monocytic cell line, and compared the results with those for other macrolides, minocycline and ofloxacin. In the presence of LPS, treatment with azithromycin (AZM) resulted in a significant decrease in LPS-induced TNF-alpha production compared to that with other antimicrobial agents. the results of phosphorylation of three MAPKs, ERK, JNK and p38, indicated that the phospho-p38 level was reduced by AZM. Ikappab-alpha, an inhibitor of NFkappab, was not disrupted by the antibiotics. LPS-induced TNF-alpha release from THP-1 cells was inhibited in the presence of KNK437, a potent 70-kDa heat shock protein (HSP-70) inhibitor. Interestingly, the induction of HSP-70 by LPS was attenuated with the concurrent addition of AZM in the cells. AZM was found to restrain TNF-alpha production by monocytes at least in part by modifying the HSp-70 and p38 related signaling pathways to LPS stimulation.
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PMID:Azithromycin reduces tumor necrosis factor-alpha production in lipopolysaccharide-stimulated THP-1 monocytic cells by modification of stress response and p38 MAPK pathway. 1962 57

The expression of chemokines is critical in leukocyte recruitment and inflammation, but the regulatory mechanisms involved remain incompletely defined. While endocrine disrupter chemicals (EDCs) are known to be ubiquitous in the environment and often associated with altered inflammatory response, their potential impact on chemokine expression in monocytes is at present unknown. To this end, the effects of EDCs on the expression of Th1- and Th2-related chemokines in a human monocytic cell line, THP-1, were investigated. THP-1 cells were pre-treated with varying concentrations of EDCs (nonylphenol and 4-octylphenol) with or without the addition of an estrogen receptor (ER) antagonist, ICI 182,780 and then stimulated by lipopolysaccharide (LPS). The levels of chemokines, CXCL10/ IFN-alpha-inducible protein 10 (IP-10, a Th1 chemokine) and monocyte-derived chemokine (MDC)/CCL22, a Th2 chemokine) were measured by ELISA. EDC-mediated signaling events and histone modifications were examined by the use of Western blotting and chromatin immunoprecipitation (ChIP) assay. Nonylphenol and 4-octylphenol were able to suppress LPS-induced MDC and IP-10 expression. This suppressive effect was not reversed by the addition of ICI 182,780. Nonylphenol and 4-octylphenol reduced LPS-induced activation of MAPK signaling pathway, MKK1/2 and ERK, concomitant with decreased levels of LPS-induced acetylated histone 4 (H4) at the IP-10 and MDC gene loci. Nonylphenol and 4-octylphenol suppressed LPS-induced MDC expression in monocytes via, at least in part, the MKK1/2-ERK MAPK pathway and histone H4 acetylation, but not the estrogen receptor.
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PMID:Suppressive effect on MDC and IP-10 expression in monocytes by endocrine disruptor chemicals. 1975 97

Tobacco may be involved in the decreased macrophage heme oxygenase-1 (HO-1) expression described in smoking-induced severe emphysema, via the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-BTB and CNC homology 1, basic leucine zipper transcription factor 1 (Bach1) pathway. We assessed in vitro effects of cigarette smoke condensate (CS) in the human monocyte/macrophage cell line (THP-1). CS exposure led to increased HO-1 and nuclear Nrf2 expression (6 h) followed by decreased HO-1 expression concomitantly with nuclear Nrf2/Bach1 ratio decrease (72h). CS-induced mitogen-activated protein kinase (MAPK) phosphorylation. Extracellular-signal-regulated kinase(1/2) (ERK(1/2)) and c-Jun NH2-terminal kinase (JNK) inhibition completely abrogated CS effects on HO-1 expression and nuclear Nrf2/Bach1 translocation. These results suggest that ERK(1/2) and JNK are involved in CS-induced biphasic HO-1 expression by a specific regulation of Nrf2/Keap1-Bach1.
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PMID:Prolonged cigarette smoke exposure decreases heme oxygenase-1 and alters Nrf2 and Bach1 expression in human macrophages: roles of the MAP kinases ERK(1/2) and JNK. 1982 48

The pathophysiological functions of proline-glutamic acid (PE)/proline-proline-glutamic acid (PPE) family of proteins of Mycobacterium tuberculosis are not well understood. In this study, we demonstrate that one of the PPE proteins, PPE18 can stimulate macrophages to secrete IL-10, known to favor a Th2 type response. The recombinant PPE18 was found to specifically interact with the TLR2 leading to an early and sustained activation of p38 MAPK, which is critical for IL-10 induction. In silico docking analyses and mutation experiments indicate that PPE18 specifically interacts with the leucine rich repeat 11 approximately 15 domain of TLR2 and the site of interaction is different from that of a synthetic lipopeptide Pam(3)CSK(4) known to activate predominantly ERK 1/2. When PMA-differentiated THP-1 macrophages were infected with a mutant Mycobacterium tuberculosis strain lacking the PPE18, produced poorer levels of IL-10 as compared with those infected with the wild-type strain. In contrast, an M. smegmatis strain overexpressing the PPE18 induced higher levels of IL-10 in infected macrophages. Our data indicate that the PPE18 protein may trigger an anti-inflammatory response by inducing IL-10 production.
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PMID:The PPE18 of Mycobacterium tuberculosis interacts with TLR2 and activates IL-10 induction in macrophage. 1988 Apr 48


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