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)

We have investigated the activation of mitogen-activated protein kinase (MAP-kinase) in KB human epidermoid carcinoma cells treated with interleukin 1 (IL-1). MAP-kinase activity was transient; the time required for activity to reach a maximal level was dependent upon the dose of IL-1, ranging from 15 minutes to 45 minutes. The level of kinase induction correlated well with dose-response curves for two characteristic IL-1-induced responses, PGE2 and IL-6 production. MAP-kinase activity returned to basal levels within 2 hours regardless of the amount of IL-1 added to the system. Exposure of KB cells to free IL-1 was accordingly restricted to periods of 2 hours or less, by replacing IL-1 with an excess of IL-1 receptor antagonist. Even after 2 hours exposure, the ability of IL-1 to induce IL-6 or PGE2 was still IL-1ra-inhibitable by more than 80%, suggesting that events downstream of, or parallel to MAP-kinase activation, requiring the continual formation of new IL-1 receptor complexes, are needed to fully elicit these responses. Two general serine/threonine kinase inhibitors, K252a and quercetin, were found to strongly inhibit MAP kinase in vivo with ED50s of c. 100 nM and 30 microM, respectively. At these concentrations, both compounds effectively inhibited IL-1-driven PGE2 and IL-6 induction without affecting general protein synthesis or secretion. Other non-selective kinase inhibitors had less effect on MAP-kinase activation or IL-1-induced biological responses. The transient activation of MAP-kinase induction correlated strikingly with activation of the transcription factor NF-kappa B. IL-1-induced NF-kappa B activation was, however, relatively insensitive to inhibition by K252a or quercetin. We suggest that MAP-kinase is likely to be a necessary, but not sufficient, intermediate in some (IL-6, PGE2 induction) but not all (NF-kappa B activation) IL-1 responses in these cells.
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PMID:Evidence that MAP (mitogen-activated protein) kinase activation may be a necessary but not sufficient signal for a restricted subset of responses in IL-1-treated epidermoid cells. 133 84

The poly(ADP-ribose) polymerase tankyrase was originally described as a telomeric protein whose catalytic activity was proposed to regulate telomere function. Subsequent studies revealed that most tankyrase is actually extranuclear, but a discordant pattern of cytoplasmic targeting was reported. Here we used fractionation and immunofluorescence to show in 3T3-L1 fibroblasts that tankyrase is a peripheral membrane protein associated with the Golgi. We further colocalized tankyrase with GLUT4 storage vesicles in the juxtanuclear region of adipocytes. Consistent with this colocalization, we found that tankyrase binds specifically to a resident protein of GLUT4 vesicles, IRAP (insulin-responsive amino peptidase). The binding of tankyrase to IRAP involves the ankyrin repeats of tankyrase and a defined sequence ((96)RQSPDG(101)) in the IRAP cytosolic domain (IRAP(1-109)). Tankyrase is a novel signaling target of mitogen-activated protein kinase (MAPK); it is stoichiometrically phosphorylated upon insulin stimulation. Phosphorylation enhances the poly(ADP-ribose) polymerase activity of tankyrase but apparently does not mediate the acute effect of insulin on GLUT4 targeting. Taken together, tankyrase is a novel target of MAPK signaling in the Golgi, where it is tethered to GLUT4 vesicles by binding to IRAP. We speculate that tankyrase may be involved in the long term effect of the MAPK cascade on the metabolism of GLUT4 vesicles.
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PMID:Tankyrase is a golgi-associated mitogen-activated protein kinase substrate that interacts with IRAP in GLUT4 vesicles. 1098 99

Platelets regulate several polymorphonuclear leukocyte (PMN) functions. We have found that thrombin-stimulated platelets potently inhibited PMN apoptosis. Cell-free supernatant from increasing concentrations of stimulated platelets inhibited PMN apoptosis in a dose-dependent manner, with an effect similar to that of corresponding concentrations of platelets. At the plateau, platelet supernatant inhibited PMN apoptosis by 54.6 +/- 6.8%, the anti-apoptotic activity being higher than that of GM-CSF and comparable to that of LPS. Neither IL-1ra nor a combination of anti-IL1alpha + betamAb affected the activity of platelet supernatant. In contrast a mAb recognizing the active form of TGF-beta1 significantly decreased this activity. Moreover, exogenous TGF-beta1 inhibited PMN apoptosis in a dose-dependent manner. The active form of this cytokine was indeed present in the supernatant of stimulated platelets at a concentration able to elicit an anti-apoptotic effect. The p38 MAPK inhibitor SB203580 prevented the anti-apoptotic effect of TGF-beta1 in a dose-dependent manner. Interestingly, it also prevented the anti-apoptotic effect of IL-1alpha, but not that of GM-CSF, LPS and dexamethasone. In conclusion, we report for the first time that PMN apoptosis is potently inhibited by platelet-released mediators, that TGF-beta1 mediates an important part of this effect, and that p38 MAPK is involved in the TGF-beta1 signaling leading to its anti-apoptotic effect. These results provide novel evidence to support the central role of platelets in inflammation.
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PMID:Polymorphonuclear leukocyte apoptosis is inhibited by platelet-released mediators, role of TGFbeta-1. 1101 75

Toll-like receptors (TLRs) are involved in human monocyte activation by lipopolysaccharide (LPS) and Staphylococcus aureus Cowan (SAC), suggesting that gram-positive and gram-negative bacteria may trigger similar intracellular events. Treatment with specific kinase inhibitors prior to cell stimulation dramatically decreased LPS-induced cytokine production. Blocking of the p38 pathway prior to LPS stimulation decreased interleukin-1alpha (IL-1alpha), IL-1ra, and tumor necrosis factor alpha (TNF-alpha) production, whereas blocking of the ERK1/2 pathways inhibited IL-1alpha, IL-1beta, and IL-1ra but not TNF-alpha production. When cells were stimulated by SAC, inhibition of the p38 pathway did not affect cytokine production, whereas only IL-1alpha production was decreased in the presence of ERK kinase inhibitor. We also demonstrated that although LPS and SAC have been shown to bind to CD14 before transmitting signals to TLR4 and TLR2, respectively, internalization of CD14 occurred only in monocytes triggered by LPS. Pretreatment of the cells with SB203580, U0126, or a mixture of both inhibitors did not affect internalization of CD14. Altogether, these results suggest that TLR2 signaling does not involve p38 mitogen-activated protein kinase signaling pathways, indicating that divergent pathways are triggered by gram-positive and gram-negative bacteria, thereby inducing cytokine production.
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PMID:Gram-positive and gram-negative bacteria do not trigger monocytic cytokine production through similar intracellular pathways. 1140 3

The putative new interleukin (IL)-1 family member IL-1F8 (IL-1eta, IL-1H2) has been shown recently to activate mitogen activated protein kinases (MAPKs), extracellular signal-regulated protein kinase (ERK1/2) and c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NFkappa B) via a mechanism that requires IL-1Rrp2 expression in cell lines. The aim of this study was to test the hypothesis that IL-1F8 contributes to brain inflammation and injury, by studying its expression and actions in the different cell types of the mouse brain in culture. Messenger RNA for IL-1F8 was detected in neurons and glia (microglial cells, oligodendrocytes progenitor cells and to a lesser extent astrocytes) by RT-PCR. Bacterial lipopolysaccharide (LPS) had no effect on IL-1F8 mRNA levels in mixed glial cultures. Recombinant mouse IL-1beta induced strong activation of ERK1/2, p38, JNK and NFkappa B, and significant release of IL-6 and PGE2, which was blocked by IL-1ra. In contrast, recombinant mouse IL-1F8 did not influence any of these parameters. These results demonstrate that CNS cells may be a source of IL-1F8, but the failure of LPS to modulate IL-1F8 mRNA expression, and of recombinant IL-1F8 to induce any of the classical IL-1 responses, suggest that this cytokine has restricted activities in the brain, or that it may act via alternative pathway(s).
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PMID:The interleukin-1-related cytokine IL-1F8 is expressed in glial cells, but fails to induce IL-1beta signalling responses. 1574 24

The recent successful introduction of the anti-cytokine biologicals Etanercept, Infliximab, Adalimumab, and Anakinra has stimulated the search for anti-cytokine small-molecules. A number of molecular targets have been identified for the development of such small molecular anti-cytokine agents. The focus of this review will be on those inhibitors of cytokine production, which target either p38 mitogen activated protein (MAP) kinase, TNF-alpha converting enzyme (TACE), or IL-1beta converting enzyme (ICE). P38 MAP kinase occupies a central role in the signaling network responsible for the upregulation of proinflammatory cytokines like interleukin 1beta (IL-1beta) and TNF-alpha, and regulates their biosynthesis at both the transcriptional and translational level. TACE and ICE are two proteases required for the processing of proTNF-alpha and proIL-1beta, respectively into their mature, proinflammatory form. Since the mid-1990s, a plethora of inhibitors of p38 MAP kinase, TACE, and ICE has been characterized in vitro, and individual representatives from all three inhibitor classes have in the meantime been advanced into clinical trials. This review will highlight the correlation between effective inhibition at the molecular target and cellular activity in functional assays of cytokine, particularly TNF-alpha and IL-1beta, production. Structure-activity relationships (SAR) will be discussed regarding activity at the respective enzyme target, but also with regard to properties required for efficient in vitro and in vivo cellular activity (e.g., oral availability, solubility, cell penetration, etc.).
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PMID:Small molecular anti-cytokine agents. 1628 77

Proinflammatory cytokines and serotonergic homeostasis have both been implicated in the pathophysiology of major psychiatric disorders. We have demonstrated that activation of p38 mitogen-activated protein kinase (MAPK) induces a catalytic activation of the serotonin transporter (SERT) arising from a reduction in the SERT Km for 5-hydroxytryptamine (5-HT). As inflammatory cytokines can activate p38 MAPK, we hypothesized that they might also activate neuronal SERT. Indeed, Interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) stimulated serotonin uptake in both the rat embryonic raphe cell line, RN46A, and in mouse midbrain and striatal synaptosomes. In RN46A cells, IL-1beta stimulated 5-HT uptake in a dose- and time-dependent manner, peaking in 20 min at 100 ng/ml. This was abolished by IL-1ra (20 ng/ml), an antagonist of the IL-1 receptor, and by SB203580 (5 microM), a p38 MAPK inhibitor. TNF-alpha also dose- and time-dependently stimulated 5-HT uptake that was only partially blocked by SB203580. Western blots showed that IL-1beta and TNF-alpha activated p38 MAPK, in an SB203580-sensitive manner. IL-1beta induced an SB203580-sensitive decrease in 5-HT Km with no significant change in Vmax. In contrast, TNF-alpha stimulation decreased 5-HT Km and increased SERT Vmax. SB203580 selectively blocked the TNF-alpha-induced change in SERT Km. In mouse midbrain and striatal synaptosomes, maximal stimulatory effects on 5-HT uptake occurred at lower concentrations (IL-1beta, 10 ng/ml; TNF-alpha, 20 ng/ml), and over shorter incubation times (10 min). As with RN46A cells, the effects of IL-1beta and TNF-alpha were completely (IL-1beta) or partially (TNF-alpha) blocked by SB203580. These results provide the first evidence that proinflammatory cytokines can acutely regulate neuronal SERT activity via p38 MAPK-linked pathways.
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PMID:The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. 1645 91

Neural precursor cells (NPCs) have been experimentally used to repair the damaged nervous system either by exogenous transplantation or by endogenous activation. In post-injury inflammation, an array of cytokines including interleukin-1beta (IL-1beta) are released by host as well as invading immune cells and increased markedly. In the present study, we investigated the effects of IL-1beta on the survival, proliferation, differentiation and migration of NPCs as well as underlying intracellular signaling pathways. NPCs derived from the E16 rat brain were expanded in neurospheres that were found to express IL-1beta, IL-1RI and IL-1RII, but not IL-1alpha and IL-1ra. IL-1beta inhibited the proliferation of NPCs in a dose-dependent manner, an effect that can be reversed by IL-1ra, an antagonist for IL-1 receptor. This inhibitory effect of IL-1beta on NPCs proliferation resulted in part from its effect on increased apoptosis of NPCs. Moreover, IL-1ra did not affect NPCs lineage fate but rather inhibited GFAP expression in differentiated astrocytes. We also found that IL-1ra had no effect on the transmigration of NPCs in vitro. Finally, we showed that the effect of IL-1beta on NPCs proliferation and differentiation appeared to be mediated by SAPK/JNK, but not ERK, P38MAPK nor NF-kappaB pathways. These findings collectively suggest that the inflammatory environment following CNS injuries may influence the ability of NPCs to repair the damage.
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PMID:Interleukin-1beta mediates proliferation and differentiation of multipotent neural precursor cells through the activation of SAPK/JNK pathway. 1782 21

Interleukin-1 (IL-1) is expressed following LTP induction and is required for long-term memory consolidation. We demonstrate that the long-term, but not short-term memory is impaired in a transgenic mouse strain overexpressing the human soluble interleukin-1 receptor antagonist (hsIL-1ra) in the brain. Overexpression of IL-1ra was found to reduce the basal as well as the novelty-induced upregulation of activity-regulated cytoskeleton-associated protein (Arc) in the dentate gyrus and in the retrosplenial cortex. Together with the finding that blocking IL-1 receptors interferes with the BDNF-ERK1/2 pathway, our data suggest an essential role played by physiological levels of IL-1 in long-term memory consolidation.
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PMID:Impaired long term memory consolidation in transgenic mice overexpressing the human soluble form of IL-1ra in the brain. 1921 Nov 54

Pro-inflammatory cytokines (PIC) impair islet viability and function by activating inflammatory pathways that induce both necrosis and apoptosis. The aim of this study was to utilize an in vitro rat islet model to evaluate the efficacy of a clinically approved IL-1 receptor antagonist (Anakinra) in blocking PIC induced islet impairment. Isolated rat islets were cultured for 48 h +/- PIC (IL-1beta, IFNgamma, and TNFalpha) and +/-IL-1ra then assayed for cellular integrity by flow cytometry, MAPK phosphorylation by proteome array, and gene expression by RT-PCR. Nitric oxide (NO) release into the culture media was measured by Griess reaction. Islet functional potency was tested by glucose stimulated insulin secretion (GSIS) and by transplantation into streptozotocin-induced diabetic NOD.scid mice. Rat islets cultured with PIC upregulated genes for NOS2a, COX2, IL6, IL1b, TNFa, and HMOX1. IL-1ra prevented the PIC induced upregulation of all of these genes except for TNFa. Inhibition of PIC induced iNOS by NG-monomethyl-L-arginine (NMMA) only blocked the increased expression of HMOX1. IL-1ra completely abrogated the effects of PIC with respect to NO production, necrosis, apoptosis, mitochondrial dysfunction, GSIS, and in vivo potency. IL-1ra was not effective at preventing the induction of necrosis or apoptosis by exogenous NO. These data demonstrate that Anakinra is an effective agent to inhibit the activation of IL-1beta dependent inflammatory pathways in cultured rat islets and support the extension of its application to human islets in vitro and potentially as a post transplant therapy.
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PMID:IL-1beta receptor blockade protects islets against pro-inflammatory cytokine induced necrosis and apoptosis. 1933 38


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