Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of various phosphodiesterase (PDE) inhibitors on anti-CD3 induced interleukin-(IL)-4 and IL-5 production of the murine T helper cell clone of type 2 phenotype D10.G4.1 (D10) has been investigated in vitro. D10 cells were incubated in the presence of drugs and anti-CD3 mAb for 16 h before measurement of cytokines in the cell supernatants by ELISA. Whereas all PDE inhibitors tested exerted minimal effects on anti-CD3 induced IL-4 production, a marked increase in IL-5 production by the non-selective PDE inhibitors IBMX, theophylline and enprofylline was observed. The action of these non-selective PDE inhibitors was mimicked by the PDE IV-selective inhibitor rolipram and in part by the PDE III-selective inhibitors motapizone and milrinone, whereas the PDE V-selective inhibitor zaprinast was inactive. Rolipram and motapizone enhanced IL-5 production in a synergistic fashion. In support of the functional importance of PDE III and IV for IL-5 synthesis in intact murine D10 cells, we have found PDE III and IV to be the predominant isoenzyme activities in corresponding cell lysates. The stimulatory effect of rolipram on IL-5 production was almost totally reversed by the protein kinase A inhibitor KT-5720. In addition, the membrane-permeable cAMP analogue 8-bromo-cAMP mimicked the stimulatory effect of PDE inhibitors on IL-5 production while leaving IL-4 levels unaffected. Both results support the view that the action of the PDE inhibitors on murine D10 cells is mediated via an elevation of intracellular cAMP.
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PMID:Effect of phosphodiesterase inhibition on IL-4 and IL-5 production of the murine TH2-type T cell clone D10.G4.1. 855 18

While it is well established that Raf-1 kinase is activated by phosphorylation in growth factor-dependent hematopoietic cell lines stimulated with a variety of hematopoietic growth factors, little is known about the biological effects of Raf-1 activation on normal hematopoietic cells. Therefore, we examined the requirement for Raf-1 in growth factor-regulated proliferation and differentiation of hematopoietic cells using c-faf antisense oligonucleotide. Raf-1 required for the proliferation of growth factor dependent cell lines stimulated by IL-2, IL-3, G-CSF, GM-CSF and EPO that bind to the hematopoietin class of receptors. Raf-1 is also required for the proliferation of cell lines stimulated by growth factors that use the tyrosine kinase containing receptor class, including SLF and CSF-1. In addition, Raf-1 is also required for IL-6, LIF- and OSM-induced proliferation whose receptors share the gp 130 subunit. In contrast to previous results which demonstrated that IL-4 could not activate Raf-1 kinase, c-raf antisense oligonucleotides also inhibited IL-4-induced proliferation of T cell and myeloid cell lines. Using normal hematopoietic cells, c-raf antisense oligonucleotides completely suppressed the colony formation of murine hematopoietic progenitors in response to single growth factors, such as IL-3, CSF-1 or GM-CSF. Further, c-raf antisense oligonucleotides inhibited the growth of murine progenitors stimulated with synergistic combinations of growth factors (required for primitive progenitor growth) including two, three and four factor combinations. In comparison to murine hematopoietic cells, c-raf antisense oligonucleotides also inhibited both IL-3 and GM-CSF-induced colony formation of CD 34+ purified human progenitors. In addition, Raf-1 is required for the synergistic response of CD 34+ human bone marrow progenitors to multiple cytokines; however, this effect was only observed when additional antisense oligonucleotides were added to the cultures at day 7 of a 14 day assay. Finally, Raf-1 is required for the synergistic response of human Mo-7e cells and of normal human fetal liver cells to five factor combinations. Thus, Raf-1 is required to transduce growth factor-induced proliferative signals in factor-dependent progenitor cells lines for all known classes of hematopoietic growth factor receptors, and is required for the growth of normal murine and human bone marrow-derived progenitors.
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PMID:The effect of c-raf antisense oligonucleotides on growth factor-induced proliferation of hematopoietic cells. 858 63

We studied the effects of beta 2-adrenoceptor agonist on IgE production in vitro in human and in vitro and in vivo in mouse. We observed that salbutamol and fenoterol potentiate the IL-4-induced IgE production from peripheral blood mononuclear cells. This effect is associated by an enhanced mRN expression for IgE. Fenoterol also potentiated, but in a lesser extent, the IgE production from purified B lymphocytes stimulated by both IL-4 and CD40, suggesting that the activity of beta 2-adrenoceptor agonist is mediated through T lymphocyte or monocyte modulation. Fenoterol also inhibited the PHA-induced IFN-gamma production by T lymphocytes. Analogues of cAMP or activator of PKA also elicited an increase in IgE production. Moreover, the effect of fenoterol on IgE production was suppressed in the presence of PKA inhibitor. Salbutamol also potentiated the IL-4-induced IgE production from murine splenocytes activated by LPS. Furthermore, mice sensitized to ovalbumin elicited increased IgE responses after daily injection of salbutamol. This was accompanied by an increased in cytokines of Th2 subtypes. Our results showed that beta 2-adrenoceptor agonist, which are currently used in the treatment of asthma, potentiate the IgE production in vitro and in vivo.
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PMID:[Effects of beta-adrenergic compounds on IgE production]. 858 26

IL-4 and IFN-gamma increase release of secretory component (SC), the polymeric IgA (plgA)-binding segment of the plgA receptor (plgAR), by the human intestinal epithelial cell line HT29. Moreover, these two cytokines synergistically increase plgA binding and cell surface staining for the receptor. To understand better the mechanism by which these cytokines regulate plgAR, we did quantitative immunoblotting using Abs against secretory component. We found that synergy occurs at the level of total cellular plgAR. Additionally, time course studies indicated that maximal receptor levels required >24-h incubation, that reaching maximal levels required at least 18 h of cytokine treatment, and that receptor levels remained elevated as long as cytokines were present. Conversely, if cytokines were removed, then cellular plgAR levels decreased with an approximate t1/2 of 20 h. Finally, synergy required the simultaneous presence of both cytokines throughout the treatment period. Direct measurement of second messengers and inhibitor studies suggest that Ca2+, cAMP, protein kinase A, and protein kinase C do not play major roles in regulating cellular plgAR levels by either cytokine, and do not contribute to the mechanism of synergy. In contrast, protein tyrosine kinase inhibitors potently inhibited all cytokine-dependent increases in total cellular plgAR. These results suggest that IL-4 and IFN-gamma increase cellular plgAR levels in HT29 cells predominantly by activating protein tyrosine kinase-dependent signaling pathways.
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PMID:IL-4 and IFN-gamma synergistically increase total polymeric IgA receptor levels in human intestinal epithelial cells. Role of protein tyrosine kinases. 864 28

To investigate the intracellular pathways leading to ETOH-induced apoptosis, thymocytes and splenic T and B cells were cultured 16 h with or without ETOH and different stimuli, and apoptotic cell death was determined. At concentrations of 0.4%-2% in culture, ETOH induced apoptosis in all three types of cells, but it had a more profound effect on thymocytes and B cells as compared with its effect on T cells. In thymocytes, ETOH-induced apoptosis was abrogated by chelation of extracellular calcium with EGTA, and inhibition of protein synthesis with CHX, or of PKC with H7 but not of PKA with HA 1004. ETOH potentiated the apoptosis of thymocytes induced with the calcium ionophore A23187 and suboptimal doses of PMA, but it had negligible effect on dAMP- and PGE2-induced apoptosis of thymocytes. In contrast to findings in thymocytes, the ETOH-induced apoptosis of T and B cells was almost completely abrogated by PMA, but not by H7 or CHX. In spleen cells, calcium chelation with EGTA triggered apoptosis. ETOH significantly inhibited EGTA-induced apoptosis of B cells but had little effect on EGTA-induced apoptosis of T cells. IL-4 reduced the ETOH-induced apoptosis of B and T cells, but it was not effective in the prevention of apoptosis of thymocytes. Inhibition of the calcium-dependent neutral protease calpain I did not rescue cells from apoptosis. Moreover, treatment with CI-I potentiated ETOH-induced apoptosis in T cells. These results suggest that both thymocytes and splenic T and B cells have relevant apoptotic pathways that can be induced by ETOH, but the mechanisms of ETOH-induced apoptosis differ in these cells.
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PMID:Different pathways of in vitro ethanol-induced apoptosis in thymocytes and splenic T and B lymphocytes. 865 90

Prostaglandin E2 (PGE2) release from activated macrophages and/or stimulation of T cells is associated with cAMP formation and activation of protein kinase A (PKA). cAMP inhibits Th1- but not Th2-cytokine production and may influence the nature of the immune response to a given antigen. Using DNA transfection and electrophoretic mobility shift assays (EMSA), we have examined the mechanisms for the transcriptional regulation of human IL-2 and IL-4 genes by PGE2. Stimulation of Jurkat cells with ionomycin and PMA in the presence of PGE2 inhibited the IL-2- but not the IL-4-promoter activity. In EMSAs, nuclear extracts from primary human T cells stimulated with ionomycin and phorbol esters in the presence of PGE2 demonstrated decreased binding at the AP-1 and NF-AT sites of the human IL-2 promoter; binding to the OCT-1 and NF-kappa B sites was not affected. These results suggest that cAMP regulates IL-2 production in human T cells by a transcriptional mechanism which involves discrete transactivating pathways for IL-2-promoter activation.
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PMID:Prostaglandin E2 inhibits the nuclear transcription of the human interleukin 2, but not the Il-4, gene in human T cells by targeting transcription factors AP-1 and NF-AT. 866 Aug 43

The authors analysed the effect of protein kinase A (PKA) activation on the protein synthesis and secretion in the T-helper 2 cell line D10.G4.1 (D10) using an assay that allows the detection of almost all secreted proteins of a cell. IL-4 and IL-10 were quantified. Three groups of secretory products could be defined. The T-cell receptor (TCR)-induced production of the first group (A) of proteins including IL-4 was enhanced by low concentrations of PKA activators. At higher concentrations the enhancement was less marked. The synthesis and secretion of a second group (B) of proteins including IL-10 remained unaffected. The production of a third group (C) of proteins was inhibited in a concentration-dependent manner. Biochemical analysis revealed a block of phospholipase C gamma (PLC gamma) activity by PKA activators. When D10 cells were stimulated by a phorbol ester plus calcium ionophore the production of group A proteins was enhanced almost fourfold, whereas production of group B proteins was unaffected by PKA activation. This effect was observed at all concentrations of various PKA activators tested. The secretion of group C proteins was no longer inhibited. The same results were obtained when analysing IL-4 and IL-10 m-RNA by Northern blotting. The data demonstrate a lymphokine specific mode of action on a single cell basis. Furthermore, it suggests that the inhibitory action of PKA in D10 cells is due partly to blocking of PLC gamma activity.
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PMID:Differential effect of the activation of protein kinase A on the protein synthesis and secretion in the T-helper 2 cell line D10.G4.1. 871 28

Lymphokines produced by non-transformed Th clones, Th1 and Th2, were classified into three groups based on their patterns of expression by different stimuli: Group I, GM-CSF and IL-2, characterized by a strict requirement of activation of both the PKC- and calcium-dependent pathways; Group II, IFN-gamma, IL-3, and IL-4, partially induced by calcium ionophore alone; and Group III, IL-5, IL-6, and IL-10, partially induced by either PMA or calcium ionophore alone. Transfection of constitutively active PKC or p21ras replaced the requirement for PMA in expression of these lymphokines, with the exception of GM-CSF. Production of Group II lymphokines was partially induced by constitutively active calcineurin. Production of Group I and II lymphokines was highly sensitive to cyclosporin A, while Group III lymphokines were relatively resistant. Addition of prostaglandin E2 (PGE2) and overexpression of catalytic subunit of protein kinase A inhibited lymphokine production in Th1 cells, but not in Th2 cells, with the exception of GM-CSF. Production of Group III lymphokines induced by PMA alone was upregulated by PGE2, but that of Group II and III lymphokines induced by calcium ionophore alone was not affected. These results suggest that one of the targets of PGE2 is downstream of the PKC-dependent pathway.
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PMID:Signal transduction in Th clones: target of differential modulation by PGE2 may reside downstream of the PKC-dependent pathway. 872 62

The effect of T-440, a selective type IV phosphodiesterase inhibitor, on cytokine production by peripheral blood mononuclear cells (PBMC) of atopic asthmatics was investigated. T-440 suppressed allergen-induced interleukin (IL)-5 production with a high potency (IC50 = 0.039 microgram/ml) and allergen-induced proliferation of PBMC (IC50 = 0.30 microgram/ml). T-440 also suppressed IL-2, IL-4 and IL-5 production by concanavalin A-activated PBMC in concentration-dependent manner. The IC50 values for the suppression of cytokine synthesis were 0.11 microgram/ml for IL-2, 0.57 microgram/ml for IL-5 and 7.7 micrograms/ml for IL-4. cAMP-elevating agents, such as PGE2, forskolin and dibutyryl cAMP, suppressed IL-2, IL-4 and IL-5 production by concanavalin A-stimulated PBMC in a manner similar to that of T-440. T-440 inhibited cAMP-phosphodiesterase activity and raised the intracellular cAMP level of PBMC in a concentration-dependent manner, suggesting that the increase of intracellular cAMP caused by T-440 results in the reduction of cytokine production. We conclude that T-440 suppressed cytokine production by peripheral T lymphocytes via the protein kinase A pathway and may be an effective modality to treat atopic diseases associated with eosinophilic inflammation.
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PMID:Interleukin-5 production by peripheral blood mononuclear cells of asthmatic patients is suppressed by T-440: relation to phosphodiesterase inhibition. 885 99

Activation of Ras GTPases is a conserved feature of antigen receptor signaling, including Fc epsilon R1 activation of mast cells. Antigenic cross-linking of the Fc epsilon R1 on mast cells results in secretion of allergic mediators and induction of immediate early and cytokine genes. Here we examine the role of Ras in coupling the Fc epsilon R1 to transcriptional regulation. The transcription factors Elk-1, an immediate early gene regulator and the nuclear factor of activated T cells (NFAT), in the context of the IL-4 gene, are identified as Ras targets in mast cells. Ras mediates diverse effects via its diverse effector pathways, which may include other members of the Ras GTPase family such as RhoA and Rac-1. We observe that Elk-1 and NFAT are targeted by distinct Ras effector pathways in mast cells. Activation of the "classical" Ras/Raf-1/MEK/ ERK cascade is necessary and sufficient for Fc epsilon R1 induction of Elk-1. Ras function is required, but not sufficient for Fc epsilon R1 induction of NFAT. However, activation or inhibition of Ras markedly shifts the antigen dose-response for Fc epsilon R1 induction of NFAT. The effector pathway for Ras activation of NFAT is not Raf-1/MEK. We identify that the Rac-1 GTPase is critical in Fc epsilon R1 regulation of NFAT, acting either in parallel with or as an effector of Ras. These data place Ras in a crucial position in mast cells, regulating disparate nuclear targets. Moreover, we identify that two GTPases, Ras and Rac-1, are important regulators of NFAT, and therefore of cytokine expression in mast cells.
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PMID:Distinct Ras effector pathways are involved in Fc epsilon R1 regulation of the transcriptional activity of Elk-1 and NFAT in mast cells. 899 40


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