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)

Perillic acid, a major metabolite of d-limonene, substantially suppressed interleukin-2 (IL-2) and IL-10 production in mitogen-activated T lymphocytes. The effects of perillic acid on cytokine secretion were selective: IL-6 and transforming growth factor-beta 1 (TGF-beta 1) generation were unchanged. In H9 T lymphoma cells, exposure to perillic acid resulted in a dose-dependent depletion of membrane-bound Ras proteins. Unlike hydroxymethyl-glutaryl-CoA reductase or protein farnesyltransferase inhibitors, perillic acid did not induce a shift of membrane-bound into cytosolic p21ras but depleted total cellular Ras proteins. Triggering of the T cell receptor (TCR) perturbs the guanine nucleotide binding cycle of p21ras and in turn induces phosphorylation and activation of mitogen-activated protein kinases (MAPK). In perillic acid-treated cells, the levels of phosphorylated but not total MAPK were also decreased in a dose-dependent manner. Taken together, we provide evidence that perillic acid interrupts signalling via the Ras/MAP kinase pathway by depleting farnesylated Ras levels, an effect which may contribute to its inhibition of IL-2 production and T cell activation.
 ...
PMID:Perillic acid inhibits Ras/MAP kinase-driven IL-2 production in human T lymphocytes. 943 75

Productive T cell activation leading to cytokine secretion requires the cooperation of multiple signaling pathways coupled to the TCR and to costimulatory molecules such as CD28. Here, we utilized two pharmacophores, PD98059 and FK506, that inhibit, respectively, mitogen-activated protein (MAP) kinase kinase 1 (MEK 1) and calcineurin, to determine the relative role of the signaling pathways controlled by these enzymes in T cell activation. Although the two compounds had distinctive effects on CD69 induction, they both suppressed T cell proliferation induced by anti-CD3 mAb, in a manner reversible by exogenous IL-2, suggesting that PD98059, like FK506, affects the production of, rather than the responsiveness to growth-promoting cytokines. Accordingly, IL-2 production by T cells stimulated with anti-CD3 mAb in conjunction with PMA or with anti-CD28 mAb was inhibited by both compounds. However, these compounds differentially affected the production of other cytokines, depending on the mode of activation. PD98059 inhibited TNF-alpha, IL-3, granulocyte-macrophage (GM)-CSF, IFN-gamma, and to a lesser extent IL-6 and IL-10 production but enhanced IL-4, IL-5, and IL-13 production induced by CD3/PMA or CD3/CD28. FK506 suppressed CD3/PMA-induced production of all cytokines examined here but to a lesser extent IL-13. FK506 also reduced CD3/CD28-induced production of IL-3, IL-4, IL-10, TNF-alpha, and IL-6 but augmented that of GM-CSF, IL-5, IFN-gamma, and IL-13. Therefore, the biochemical targets of PD98059 and FK506 contribute differently to the production of various cytokines by T cells, which may have implications for the therapeutic manipulation of this production.
 ...
PMID:Inhibition of T cell activation by pharmacologic disruption of the MEK1/ERK MAP kinase or calcineurin signaling pathways results in differential modulation of cytokine production. 951 Jan 55

TNF-alpha or IL-10 has been implicated to reversibly regulate physiological states of dendritic cells (DCs). However, little is known about dual stimulations of these cytokines on DC properties and the intracellular signaling events that are responsible for the regulation of these states. Here, we show that a family of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase 2 (ERK2), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38mapk, are potentially involved in IL-10-mediated selective suppression of TNF-alpha-induced changes of the monocyte-derived DC properties. TNF-alpha induced the cluster formation of the cells and the enhancement of cell surface expression levels of CD83, CD86, and HLA-DR, and T cell stimulatory capacity, whereas the capacities for the endocytosis and the chemotactic migration were suppressed in these cells. Treatment of monocyte-derived DCs with IL-10 resulted in the reduction of the cell surface expression levels of CD86, HLA-DR, and T cell stimulatory capacity, whereas both endocytic and chemotactic migratory capacities were increased by IL-10. Dual stimulations of monocyte-derived DCs with TNF-alpha and IL-10 selectively antagonized their respective effects on these DC properties. TNF-alpha induced tyrosine phosphorylation and enzymatic activation of ERK2, SAPK/JNK, and p38mapk, whereas IL-10 did not induce these events. Dual stimulations of TNF-alpha plus IL-10 abolished TNF-alpha-induced changes of these MAPKs in DCs. These results suggest that the blockage in the MAPKs cascades contributes to IL-10-mediated repression of TNF-alpha-induced changes of DC properties.
 ...
PMID:Extracellular signal-regulated kinase, stress-activated protein kinase/c-Jun N-terminal kinase, and p38mapk are involved in IL-10-mediated selective repression of TNF-alpha-induced activation and maturation of human peripheral blood monocyte-derived dendritic cells. 1020 4

Recently, it has been demonstrated that the CD40 receptor is constitutively expressed on cultured microglia at low levels. Ligation of CD40 by CD40 ligand on these cells results in microglial activation, as measured by TNF-alpha production and neuronal injury. However, the intracellular events mediating this effect have yet to be investigated. We report that ligation of microglial CD40 triggers activation of p44/42 mitogen-activated protein kinase (MAPK). This effect is evident 30 min posttreatment, and progressively declines thereafter (from 30 to 240 min). Phosphorylated p38 MAPK is not observed in response to ligation of microglial CD40 across the time course examined. Inhibition of the upstream activator of p44/42 MAPK, mitogen-activated protein/extracellular signal-related kinase kinase 1/2, with PD98059, decreases phosphorylation of p44/42 MAPK and significantly reduces TNF-alpha release following ligation of microglial CD40. Furthermore, cotreatment of microglial cells with CD40 ligand and TGF-beta1 or IL-10, or both, inhibits CD40-mediated activation of p44/42 MAPK and production of TNF-alpha in a statistically interactive manner. Taken together, these data show that ligation of microglial CD40 triggers TNF-alpha release through the p44/42 MAPK pathway, an effect that can be opposed by TGF-beta1 and IL-10.
 ...
PMID:Ligation of microglial CD40 results in p44/42 mitogen-activated protein kinase-dependent TNF-alpha production that is opposed by TGF-beta 1 and IL-10. 1058 56

Extracellular purines, including adenosine and ATP, are potent endogenous immunomodulatory molecules. Inosine, a degradation product of these purines, can reach high concentrations in the extracellular space under conditions associated with cellular metabolic stress such as inflammation or ischemia. In the present study, we investigated whether extracellular inosine can affect inflammatory/immune processes. In immunostimulated macrophages and spleen cells, inosine potently inhibited the production of the proinflammatory cytokines TNF-alpha, IL-1, IL-12, macrophage-inflammatory protein-1alpha, and IFN-gamma, but failed to alter the production of the anti-inflammatory cytokine IL-10. The effect of inosine did not require cellular uptake by nucleoside transporters and was partially reversed by blockade of adenosine A1 and A2 receptors. Inosine inhibited cytokine production by a posttranscriptional mechanism. The activity of inosine was independent of activation of the p38 and p42/p44 mitogen-activated protein kinases, the phosphorylation of the c-Jun terminal kinase, the degradation of inhibitory factor kappaB, and elevation of intracellular cAMP. Inosine suppressed proinflammatory cytokine production and mortality in a mouse endotoxemic model. Taken together, inosine has multiple anti-inflammatory effects. These findings, coupled with the fact that inosine has very low toxicity, suggest that this agent may be useful in the treatment of inflammatory/ischemic diseases.
 ...
PMID:Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock. 1062 51

Polyamines are endogenous immunomodulatory molecules. Recent studies revealed that polyamines suppress the production of proinflammatory cytokines and nitric oxide. In the present study, we investigated the effect of the polyamines spermine, spermidine, and putrescine on the production of interleukin (IL)-12 p40, IL-10, and interferon (IFN-gamma) in mouse peritoneal macrophages and spleen cell suspensions. Spermine, but not spermidine or putrescine, suppressed, in a concentration-dependent manner, the production of IL-12 p40 by lipopolysaccharide (LPS)-stimulated macrophages. The effect of spermine was post-transcriptional, because steady-state levels of messenger ribonucleic acid (mRNAs) for IL-12 (p35 and p40) were not affected. In contrast to its inhibitory effect on IL-12 p40, spermine (0.3-3 microM) augmented IL-10 production. The down-regulation of IL-12 p40 by spermine was independent of enhancement of IL-10 by this agent, for spermine retained its ability to suppress IL-12 production in peritoneal macrophages obtained from IL-10-deficient mice. The alterations in cytokine production by spermine did not involve an effect on early intracellular pathways of LPS signal transduction, including the p38 or p42/44 mitogen-activated protein kinases, or the c-jun terminal kinase. In spleen cell suspensions, spermine suppressed the release of IFN-gamma induced either by LPS or anti-CD3 antibody. In summary, spermine exerts anti-inflammatory effects by suppressing IL-12 and IFN-gamma and by augmenting the production of IL-10.
 ...
PMID:Spermine differentially regulates the production of interleukin-12 p40 and interleukin-10 and suppresses the release of the T helper 1 cytokine interferon-gamma. 1094 58

Interleukin 12 (IL-12) is a crucial cytokine in the regulation of T helper 1 vs. T helper 2 immune responses. In the present study, we investigated the effect of the endogenous purine nucleoside adenosine on the production of IL-12. In mouse macrophages, adenosine suppressed IL-12 production. Although the order of potency of adenosine receptor agonists suggested the involvement of A2a receptors, data obtained with A2a receptor-deficient mice showed that the adenosine suppression of IL-12 and even TNF-alpha production is only partly mediated by A2a receptor ligation. Studies with adenosine receptor antagonists or the adenosine uptake blocker dipyridamole showed that adenosine released endogenously also decreases IL-12. Although adenosine increases IL-10 production, the inhibition of IL-12 production is independent of the increased IL-10. The mechanism of action of adenosine was not associated with alterations of the activation of the p38 and p42/p44 mitogen-activated protein kinases or the phosphorylation of the c-Jun terminal kinase. Adenosine failed to affect steady-state levels of either IL-12 p35 or p40 mRNA, but augmented IL-10 mRNA levels. In summary, adenosine inhibits IL-12 production via various adenosine receptors. These results support the notion that adenosine-based therapies might be useful in certain autoimmune and/or inflammatory diseases.
 ...
PMID:Adenosine inhibits IL-12 and TNF-[alpha] production via adenosine A2a receptor-dependent and independent mechanisms. 1102 91

When HLA-DR, -DQ, and -DP were cross-linked by solid-phase mAbs, monocytes produced monokines and only anti-DR markedly activated mitogen-activated protein (MAP) kinase extracellular signal-related kinase, whereas anti-DR, anti-DQ, and anti-DP all activated MAP kinase p38. Activation of extracellular signal-related kinase was not inhibited by neutralizing Ab to TNF-alpha. Anti-DR and DR-restricted T cells stimulated monocytes to produce relatively higher levels of proinflammatory monokines, such as IL-1beta, whereas anti-DQ/DP and DQ-/DP-restricted T cells stimulated higher levels of anti-inflammatory monokine IL-10. IL-10 production was abrogated by the p38 inhibitor SB203580, but rather enhanced by the MAP/extracellular signal-related kinase kinase-I-specific inhibitor PD98059, whereas IL-1beta was only partially abrogated by SB203580 and PD98059. Furthermore, DR-restricted T cells established from PBMC, which are reactive with mite Ags, purified protein derivative, and random 19-mer peptides, exhibited a higher IFN-gamma:IL-4 ratio than did DQ- or DP-restricted T cells. These results indicate that HLA-DR, -DQ, and -DP molecules transmit distinct signals to monocytes via MAP kinases and lead to distinct monokine activation patterns, which may affect T cell responses in vivo. Thus, the need for generation of a multigene family of class II MHC seems apparent.
 ...
PMID:Monocytes are differentially activated through HLA-DR, -DQ, and -DP molecules via mitogen-activated protein kinases. 1116 Feb 73

Concerning schistosomiasis, little is known about the intracellular signaling response of human peripheral blood mononuclear cells (PBMC) to Schistosoma mansoni antigens. To understand the critical role of protein tyrosine kinases (PTKs) in PBMC activation by S. mansoni antigens, we investigated how inhibition of PTKs by genistein, a tyrosine kinase inhibitor, affects proliferation, cytokine production and activation of mitogen-activated protein kinases (MAPKs). Our studies showed that PTKs have an important role in proliferation of PBMC from chronic schistosomiasis patients as cells stimulated with S. mansoni soluble antigens in the presence of genistein had an impaired proliferation. In contrast, PTK inhibition failed to cause any effect on MAPKs activity. We also evaluated the cytokine production for interleukin (IL)-2, interferon gamma (IFN-gamma), and IL-10 in culture supernatants of PBMC treated with or without PTKs inhibitor. Our results show that PBMC from chronic patients produced a high amount of IL-10 when stimulated with soluble egg antigen preparation (SEA), however, the amount produced of IL-2 and IFN-gamma was not significant. In the presence of PTKs inhibitor only the production of IL-10 was decreased. The findings suggest that PTKs are involved on signal transduction pathway for PBMC activation, but may not be an absolute requirement for all signaling responses to S. mansoni antigens.
 ...
PMID:Human peripheral blood mononuclear cells stimulated by Schistosoma mansoni antigens: association between protein tyrosine kinases, mitogen-activated protein kinases and cytokine production. 1122 66

The clinical course of mycobacterial infections is linked to the capacity of pathogenic strains to modulate the initial antimycobacterial response of the macrophage. To elucidate some of the mechanisms involved, we studied early signal transduction events leading to cytokine formation by human monocyte-derived macrophages (MDM) in response to clinical isolates of Mycobacterium avium. TNF-alpha production induced by M. avium was inhibited by anti-CD14 mAbs, but not by Abs against the macrophage mannose receptor. Analysis of mitogen-activated protein (MAP) kinase activation (extracellular signal-regulated kinase 1/2, p38, and c-Jun NH(2)-terminal kinase) showed a rapid phosphorylation of all three subfamilies in response to M. avium, which was inhibited by anti-CD14 Abs. Using highly specific inhibitors of p38 (SB203580) and MAP kinase kinase-1 (PD98059), we found that activation of the extracellular signal-regulated kinase pathway, but not of p38, was essential for the M. avium-induced TNF-alpha formation. In contrast, IL-10 production was abrogated by the p38 inhibitor, but not by the MAP kinase kinase-1 inhibitor. In conclusion, M. avium-induced secretion of TNF-alpha and IL-10 by human macrophages is differentially regulated at the level of MAP kinase activity.
 ...
PMID:Mycobacteria-induced TNF-alpha and IL-10 formation by human macrophages is differentially regulated at the level of mitogen-activated protein kinase activity. 1154 23


1 2 3 4 5 6 7 8 9 10 Next >>