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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An increasing body of evidence suggests that catecholamines (CAs) do not only cause a general immunosuppression as previously believed, but suppress cellular immunity and boost humoral response. CAs can inhibit T helper 1 cells, T cytotoxic cells, natural killer cells and monocytes, but enhance T helper 2 cells and B cells through their direct regulation of these immune cells. In addition, CAs may modulate the gene transcription for cytokines in immune cells through stimulation of beta 2-adrenoreceptors and increase of cAMP, subsequently, activation of protein kinase A and alteration of the activity of nuclear transcription factors. Through these molecular mechanisms, the production of interleukin-2 (IL-2), tumor necrosis factor-alpha and IL-12 is decreased, but the production of IL-6, IL-10 and IL-4 is increased.
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PMID:[Cellular and molecular mechanisms of regulation of immune functions by catecholamines]. 1499 10

This study shows that two cAMP elevating agents, dibutyryl-cAMP (dbcAMP) and forskolin, regulate the expression of several cytokines and inducible nitric oxide synthase (iNOS) in a different manner. Both dbcAMP and forskolin repressed lipopolysaccharide (LPS)-induced TNF-alpha expression and enhanced anti-inflammatory cytokine IL-10 level in the BV2 microglia. In contrast, they differentially regulated the iNOS, IL-6 and IL-1beta expression levels. DbcAMP increased the IL-1beta level without affecting either the IL-6 or iNOS expression, whereas forskolin repressed the IL-6 and iNOS expression level without affecting IL-1beta in the LPS-stimulated microglia. Treatment with H89, a specific inhibitor of protein kinase A (PKA), revealed that an enhancement in the IL-10 and IL-1beta levels by dbcAMP or forskolin totally depends on the PKA pathway, while changes in the other cytokines and iNOS are independent or only partially dependent on the PKA pathway. These results suggest the diverse regulation of the inflammatory reactions depending on different cAMP elevating agents.
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PMID:Differential regulation of inducible nitric oxide synthase and cytokine gene expression by forskolin and dibutyryl-cAMP in lipopolysaccharide-stimulated murine BV2 microglial cells. 1503 26

In this study we compared the activation of monocytes by different bacterial products via Toll-like receptors (TLR), and by different proinflammatory mediators. In response to TLR-2, -4 and -5 engagement, approximately 50% of monocytes produced TNF-alpha, compared to only 5% after induction with IFN-gamma or GM-CSF. Furthermore, a small proportion of monocytes produced IL-10 after stimulation via TLR, but not after stimulation with cytokines. Both TLR-ligands and inflammatory cytokines induced the expression of CD25, CD69, CD80 and, surprisingly, also of CD83, commonly regarded as an activation marker for mature dendritic cells (DC). Conversely, TLR-ligands downregulated CD38, CD86 and ICOS-L. Importantly, signaling lymphocytic activation molecule (SLAM; CD150) was identified as a monocyte activation marker that could be induced ex novo via TLR-2, -4 and -5, but not by single stimulation with monocyte activators like IL-1, TNF-alpha, IFN-beta, IFN-gamma, GM-CSF or CD40-L. SLAM expression was transient and required mitogen activated protein kinase (MAPK) p38, but not ERK or JNK, and was surprisingly independent of NF-kappaB. SLAM+ monocytes, which are absent in blood, were detected in spleen and tonsils, where they could be localized to T-cell areas and germinal centers. Together, by comparing the response of monocytes to TLR-ligands and inflammatory cytokines, we have identified a monocyte activation marker, SLAM, which differs in its inducibility from other monocyte activation markers. SLAM+ monocytes and macrophages were identified for the first time in vivo. Their presence might be a sign of innate immune activation.
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PMID:Distinct responses of monocytes to Toll-like receptor ligands and inflammatory cytokines. 1509 75

Enhanced adrenergic stimulation and catecholamine release are important components of the pathophysiology of sepsis. Under physiological conditions, adrenergic stimulation has been shown to be a negative regulator of proinflammatory cytokine production through increasing IL-10 production. Here we have investigated if adrenergic stimulation similarly inhibits TNF-alpha and IL-6 production by splenic macrophages isolated from a polymicrobial sepsis model. Male B(6)D(2)F(1) mice were subjected to sham (S), laparotomy (Lap), and cecal ligation and puncture (CLP) under anesthesia. Splenic macrophages were isolated 72 h after the initial injury and were stimulated with endotoxin (LPS) in the presence and absence of epinephrine. Compared with S and Lap, splenic macrophages from the CLP group produced significantly less TNF-alpha and IL-6 and more IL-10 when stimulated with LPS. Macrophage cultures from CLP animals incubated with either epinephrine or IL-10 for 2 h had significantly reduced TNF-alpha and IL-6 release in response to LPS. However, similar cultures pretreated with IL-10 antibody before the addition of exogenous epinephrine failed to reverse the attenuation of LPS-stimulated cytokines. Pretreatment of macrophage cultures with beta(2)- (ICI-118551) but not beta(1)-adrenergic (atenolol) receptor antagonists reversed the epinephrine-mediated cytokine attenuation following LPS treatment. Data are also presented that demonstrate the involvement of protein kinase A activation with adrenergic agonist but not with IL-10 stimulation. Taken together, these findings suggest that adrenergic mechanisms may influence peripheral tissue macrophage inflammatory cytokine response following trauma and sepsis, independent of the effects of IL-10.
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PMID:Adrenergic modulation of splenic macrophage cytokine release in polymicrobial sepsis. 1515 6

Secretion of proinflammatory mediators by activated macrophages plays an important role in the immune response to Trypanosoma cruzi. We have previously reported that AgC10, a glycosylphosphatidylinositol-anchored mucin from T. cruzi, inhibits TNF secretion by activated macrophages (de Diego, J., Punzon, C., Duarte, M. and Fresno, M., Alteration of macrophage function bya Trypanosoma cruzi membrane mucin. J. Immunol. 1997. 159: 4983-4989). In this report we have further investigated the molecular mechanisms underlying this inhibition. AgC10 inhibited TNF, IL-10 and cyclooxygenase-2 (COX-2) synthesis by macrophages activated with LPS or LPS plus IFN-gamma in a dose-dependent manner. AgC10 did not affect other aspects of macrophage activation induced by LPS, such as inducible nitric oxide synthase (iNOS) expression. AgC10 also had no effect on TNF or COX-2 transcription or the induction of their promoters but inhibited the stability of TNF and COX-2 mRNA, which are regulated post-transcriptionally by the mitogen-activated protein kinase (MAPK) p38 pathway. AgC10 was found to inhibit both the activation and the activity of p38 MAPK, since MAPK activated protein kinase-2 (MAPKAP-K2 or MK-2) phosphorylation was also strongly inhibited. This led to TNF and COX-2 mRNA destabilization. In contrast, AgC10 did not affect p38 activation induced by TNF. Furthermore, AgC10 inhibition must lie upstream in the MAPK activation pathway by LPS, since this mucin also inhibited extracellularly regulated kinase (ERK) and Jun kinase (JNK)activation.
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PMID:AgC10, a mucin from Trypanosoma cruzi, destabilizes TNF and cyclooxygenase-2 mRNA by inhibiting mitogen-activated protein kinase p38. 1516 40

In the hope of identifying agents of therapeutic value in tissue inflammation, we tested ethanolic extracts of six Chinese herbs for their effects on human peripheral blood mononuclear cells (PBMC) proliferation in vitro. The results indicated that the extracts from Nelumbo nucifera Gaertn, used in treatment of tissue inflammation in traditional Chinese medicine, inhibited PBMC proliferation activated with phytohemagglutinin (PHA). By a bioassay-guided fractionation procedure, NN-B-4 identified from N. nucifera ethanolic extracts significantly suppressed activated PBMC proliferation. The inhibitory action of NN-B-4 did not involve direct cytotoxicity. In an attempt to further localize the point in the PBMC proliferation where arrest occurred, a set of key regulatory events leading to the cell proliferation, including cell cycle progression, production and gene expression of interleukin-2 (IL-2), IL-4, IL-10, and interferon-gamma (IFN-gamma) was examined. Cell cycle analysis indicated that NN-B-4 arrested the cell cycle progression of activated PBMC from the G1 transition to the S phase. The cyclin-dependent kinase (cdk) 4 mRNA expression in PBMC stimulated with PHA was reduced by NN-B-4. NN-B-4 suppressed, in activated PBMC, the production and mRNA expression of IL-2, IL-4, IL-10, and IFN-gamma in a dose-dependent fashion. The suppressant effects of NN-B-4 on proliferation of PBMC activated by PHA therefore appear to be mediated, at least in part, through inhibition of early transcripts of PBMC, especially those of important IL-2, IFN-gamma, and cdk4 and arrest of cell cycle progression in the cells.
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PMID:The extracts from Nelumbo Nucifera suppress cell cycle progression, cytokine genes expression, and cell proliferation in human peripheral blood mononuclear cells. 1517 79

Excessive proinflammatory cytokine and NO production by activated microglia play a role in neurodegenerative disorders. In this study, we found that a new compound KL-1037 suppressed LPS-induced NO release/inducible nitric oxide synthase expression in BV2 mouse microglial cells. In addition, KL-1037 prominently diminished LPS-induced production of pro-inflammatory cytokines such as TNF-alpha, IL-1 beta and IL-6, while it increased anti-inflammatory IL-10 and TGF-beta 1 production. By RNase protection assay and RT-PCR, we showed that KL-1037 regulated iNOS and cytokines at transcriptional or post-transcriptional level. Further analysis of molecular mechanisms revealed that KL-1037 prominently increased intracellular cAMP levels and potentiated LPS-induced pCREB expression. However, LPS-induced MAP kinase or NF-kappa B activities were slightly or little changed by KL-1037. Treatment with cAMP antagonist or IL-10 neutralizing antibody completely reversed upregulation of IL-10 and partially repression of TNF-alpha or NO induced by KL-1037. These data suggest that microglial inactivation by KL-1037 is at least in part due to activation of PKA pathway and/or upregulation of IL-10. Thus, repressing proinflammatory cytokines and iNOS gene expression in activated microglia by KL-1037 may provide potential therapeutic strategies for various neurodegenerative diseases including ischemic cerebral disease.
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PMID:A new anti-inflammatory agent KL-1037 represses proinflammatory cytokine and inducible nitric oxide synthase (iNOS) gene expression in activated microglia. 1522 3

B-cell chronic lymphocytic leukemia (B-CLL), a clonal expansion of B CD5+ cells, is the most frequent type of adult leukemia in western countries. Accumulation of neoplastic B-cells is caused not by their higher proliferation rate, but by their prolonged life-span due to dysregulation of apoptosis. Many proteins act as inducers or inhibitors in controlling apoptosis. A high level of antiapoptotic BCL-2 protein is detected in B cells of B-CLL. Other factors, such as NF-kappaB, PI-3K and PKC, are also involved in the inhibition of malignant cell apoptosis. A high level of p27kip1, an inhibitor of cyclin-dependent kinase that correlates with the degree of in vitro apoptosis, is found in B-CLL cells. The autologous interaction between BAFF, APRIL, and their ligands may also be involved in apoptosis inhibition in B-CLL. Some external factors e.g. cytokines, may suppress apoptosis of malignant cells. IL-4, IL-2, IFN-gamma, and TNF are proven inhibitors, while IL-5 and IL-10 are inducers of apoptosis of these cells. Even though there are reports characterizing some mechanisms of B-CLL cell apoptosis, relatively less is still known about the complex regulation of this process. This requires more precise research, as new anti-leukemic drugs influence the regulation of apoptosis of neoplastic B lymphocytes.
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PMID:[Apoptosis in pathogenesis of B-cell chronic lymphocytic leukemia]. 1522 9

In anergic T cells, T-cell receptor (TCR)-mediated responses are functionally inactivated by negative regulatory signals whose mechanisms are poorly understood. Here, we show that CD4(+) T cells anergized in vivo by superantigen Mls-1(a) express a scaffolding protein, transforming growth factor beta-activated protein kinase 1-binding protein 1 (TAB1), that negatively regulates TCR signaling through the activation of mitogen-activated protein kinase p38 alpha. TAB1 was not expressed in naive and activated CD4(+) T cells. Inhibition of p38 activity in anergic T cells by a chemical inhibitor resulted in the recovery of interleukin 2 (IL-2) and the inhibition of IL-10 secretion. T-cell hybridoma 2B4 cells transduced with TAB1-containing retrovirus (TAB1-2B4 cells) showed activated p38 alpha, inhibited extracellular signal-regulated kinase (ERK) activity, culminating in reduced IL-2 levels and increased IL-10 production. The use of a p38 inhibitor or cotransfection of a dominant-negative form of p38 in TAB1-2B4 cells resulted in the recovery of ERK activity and IL-2 production. These results imply that TAB1-mediated activation of p38 alpha in anergic T cells regulates the maintenance of T-cell unresponsiveness both by inhibiting IL-2 production and by promoting IL-10 production.
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PMID:Regulation of the maintenance of peripheral T-cell anergy by TAB1-mediated p38 alpha activation. 1620 Jun 88

This study investigated the effect of in vitro exposure to caffeine, and its major metabolite paraxanthine, at concentrations relevant to typical caffeine consumption in humans, on lipopolysaccharide (LPS)-stimulated cytokine production in human whole blood. In addition, a role for the cyclic AMP/protein kinase A (PKA) pathway in the immunomodulatory effect of caffeine was investigated. Diluted whole blood (taken following >/=15 h abstinence from caffeine-containing food and beverages) was preincubated with caffeine or paraxanthine (10-100 microM) and stimulated with LPS (1 proportional, variant g/ml) for 24 h. The proinflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-12, and the antiinflammatory cytokine IL-10 were measured in cell-free supernatants. Whilst caffeine and paraxanthine had little or no effect on IL-10, IL-1beta, or IL-12 production, TNF-alpha production was suppressed in all individuals studied. The effect was statistically significant at 100 microM and consistent across seven experiments performed. Although not statistically significant, a similar effect was observed with paraxanthine. Caffeine (100 microM) also increased intracellular cyclic AMP concentrations in LPS-stimulated monocytes isolated from whole blood. Moreover, the effect of caffeine on TNF-alpha production was abolished by pretreatment with the protein kinase A inhibitor Rp-8-Br-cAMPS (10(-4) and 10(-5)M). To conclude, this study demonstrates that concentrations of caffeine that are relevant to human consumption consistently suppress production of the proinflammatory cytokine TNF-alpha in human blood and that this effect is mediated by the cyclic AMP/protein kinase A pathway.
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PMID:Caffeine suppresses TNF-alpha production via activation of the cyclic AMP/protein kinase A pathway. 1531 38


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