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)

T2, an extract of Tripterygium wilfordii Hook F, has been reported to be effective in the treatment of a variety of autoimmune diseases, including rheumatoid arthritis. Previous studies have shown that T2 inhibited mitogen- or antigen-induced proliferation of human peripheral blood T cells and B cells, IL-2 production by T cells and Ig production by B cells. In contrast, T2 did not affect monocyte functions, such as IL-1 production and antigen presentation. The current studies sought to localize the immunosuppressive action of T2 more precisely. Results show that T2 prevented [3H]-uridine uptake by mitogen-stimulated T cells and arrested them in the early GI phase of the cell cycle. The inhibitory effects of T2 could be partially overcome by costimulating PHA activated T cells with PMA and completely nullified by costimulation with PMA plus a monoclonal antibody to CD28. Moreover, T2 had no effect on expression of IL-2R or the transferrin receptor (CD71), but inhibited production of a number of cytokines, including IL-2 and IFN-gamma by activated T cells. T2 suppressed IL-2 mRNA levels, but not IL-2R mRNA levels, in activated T cells. T2-mediated inhibition reflected suppression of IL-2 gene transcription as indicated by suppression of the expression of a reporter gene driven by the IL-2 promoter. T2 had little inhibitory effect on either IL-2 gene expression or cell cycle progression when added after initial mitogenic stimulation, indicating that an early step in the cascade of activation events was inhibited. However, initial activation events including protein tyrosine phosphorylation, the generation of diacylglycerol, IP3, and the translocation of protein kinase C were not inhibited by T2. Moreover, T2 did not inhibit the phosphatase activity of calcineurin. These results have localized the effect of T2 to a step in the T cell activation cascade after initial second messenger generation, tyrosine phosphorylation and protein kinase activation, but before IL-2 gene transcription.
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PMID:The Chinese herbal remedy, T2, inhibits mitogen-induced cytokine gene transcription by T cells, but not initial signal transduction. 855 49

A new p56lck tyrosine kinase inhibitor WIN 61651 [1,4-dihydro-7-(4-methyl-1-piperizinyl)-1-(4-(4-methyl-1-piperi zinyl))phenyl- 4-oxo-3-quinolinecarboxamide) is described. WIN 61651, which is competitive with ATP, demonstrates selectivity for the lymphoid restricted tyrosine kinase p56lck over serine/threonine kinases, such as protein kinase C and protein kinase A, and over some other tyrosine kinases, including erbB2, epidermal growth factor receptor, and insulin receptor; however, it is equipotent for inhibition of p56lck and the platelet derived growth factor receptor tyrosine kinases. WIN 61651 inhibits p56lck activity in cell-free assays, tyrosine kinase activity in a T lymphocytic cell line, and T cell activation, as measured by IL-2 production by purified CD4 positive peripheral blood T lymphocytes and the mixed lymphocyte reaction. WIN 61651 constitutes a new tool for studies on the role for tyrosine kinases in lymphocyte function.
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PMID:Inhibition of T lymphocyte activation by a novel p56lck tyrosine kinase inhibitor. 858 49

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

Rapamycin has potent immunosuppressive properties reflecting its ability to disrupt cytokine signaling that promotes lymphocyte growth and differentiation. In IL-2-stimulated T cells, rapamycin impedes progression through the G1/S transition of the proliferation cycle, resulting in a mid-to-late G1 arrest. Two major biochemical alterations underlie this mode of action. The first one affects the phosphorylation/activation of the p70 S6 kinase (p70s6k), an early event of cytokine-induced mitogenic response. By inhibiting this enzyme, whose major substrate is the 40S ribosomal subunit S6 protein, rapamycin reduces the translation of certain mRNA encoding for ribosomal proteins and elongation factors, thereby decreasing protein synthesis. A second, later effect of rapamycin in IL-2-stimulated T cells is an inhibition of the enzymatic activity of the cyclin-dependent kinase cdk2-cyclin E complex, which functions as a crucial regulator of G1/S transition. This inhibition results from a prevention of the decline of the p27 cdk inhibitor, that normally follows IL-2 stimulation. To mediate these biochemical alterations, rapamycin needs to bind to intracellular proteins, termed FKBP, thereby forming a unique effector molecular complex. However, neither(p70s6k) inhibition, nor p27-induced cdk2-cyclin E inhibition are directly caused by the FKBP-rapamycin complex. Instead, this complex physically interacts with a novel protein, designated "mammalian target of rapamycin" (mTOR), which has sequence homology with the catalytic domain of phosphatidylinositol kinases and may therefore be itself a kinase. mTOR may act upstream of (p70s6K) and cdk2-cyclin E in a linear or bifurcated pathway of growth regulation. Molecular dissection of this pathway should further unravel cytokine-mediated signaling processes and help devise new immunosuppressants.
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PMID:Mechanism of action of the immunosuppressant rapamycin. 859 3

Cyclic AMP (cAMP)-dependent protein kinase A (PKA) is known to have both negative and positive effects on the activation mechanisms of T lymphocytes. The authors have analysed the effect of increased cAMP on the activation of NF-kappa B transcription factor. This factor controls the expression of several genes (e.g. IL-2 and IL-2 receptor) involved in the activation and proliferation of T cells. The authors found that elevation of intracellular cAMP in Jurkat T leukaemia cells activated with phorbol ester (PDBu)/calcium ionophore (A23187) increased the DNA-binding of NF-kappa B as detected by the electrophoretic mobility shift assay (EMSA). Analysis of the subunit composition of the DNA-binding complex indicated that the amount of c-Rel was enhanced while RelA was decreased. Analysis of the effect of elevated cAMP on the degradation of I kappa B-alpha and I kappa B-beta did not reveal an essential change in degradation kinetics of these inhibitor proteins. The elevation of cAMP did not increase the synthesis of c-Rel, but it enhanced the nuclear localization of this protein. Transfection of Jurkat cells with a plasmid kB/TK10-CAT indicated that the increased DNA-binding of c-Rel containing complexes seen in EMSA was also functional. These data imply that the strong and long-lasting c-Rel nuclear localization and DNA-binding induced by protein kinase A is not due to increased c-Rel synthesis or enhanced degradation of the I kappa B inhibitors. Therefore, a direct phosphorylation of the c-Rel protein is the most plausible explanation for these observations. Taken together, these results suggest that cAMP is able to regulate the expression of NF-kappa B-dependent genes in T cells by modifying the composition and subunit activity of NF-kappa B.
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PMID:Activation of the protein kinase A increases the DNA-binding and transcriptional activity of c-Rel in T cells. 865 53

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

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

Anti-CD2 monoclonal antibody (mAb) can act synergistically with anti-CD3 to produce tolerance and diminish the anti-CD3-induced cytokine syndrome. Since interleukin(IL)-2 production and IL-2 receptor (IL-2R; CD25) expression are important determinants of CD3-driven T cell activation, the effects of anti-CD2 on anti-CD3-induced CD25 expression and IL-2 production were analyzed and related mechanistically to CD2-stimulated cAMP signaling with an in vitro model of T cell activation. The anti-CD2 mAb, 12-15, alone had no effect on splenic T cell CD25 expression and IL-2 production, while the anti-CD3 mAb, 145-2C11, caused significant increases in both CD25 expression and IL-2 production. The addition of anti-CD2 inhibited anti-CD3-induced increases in CD25 and IL-2. The inhibitory signal delivered by anti-CD2 was effective in many forms of T cell activation, since other stimuli which increased CD25, such as concanavalin A, phytohemagglutinin, and Staphylococcal enterotoxin B (SEB), could also be inhibited by anti-CD2. The inhibitory effect of anti-CD2 on CD25 could not be reversed by high doses of supplemental IL-2 added to the culture. Anti-CD2 increased cytoplasmic cAMP in a dose- and time-dependent manner. Reagents that increased cytoplasmic cAMP such as forskolin, cholera toxin, and 3'-isobutyl-1-methylxanthine could mimic the inhibitory effect of anti-CD2 on anti-CD3-driven CD25 expression. Anti-CD2 also increased the activity of cAMP-dependent protein kinase (PKA). H8, a PKA antagonist, blocked the inhibitory effect of anti-CD2 on CD25 expression, further confirming the role of PKA in CD2-induced negative signaling. The use of paired agonists to PKA demonstrated that a type I PKA was the preferential enzyme isoform stimulated by CD2 ligation. These findings show that increased cAMP and PKA activity mediate anti-CD2-induced suppression of anti-CD3-driven IL-2 production and CD25 expression, and provide mechanisms for anti-CD2-induced immunosuppression and inhibition of the cytokine syndrome associated with anti-CD3 treatment.
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PMID:Increased cAMP and cAMP-dependent protein kinase activity mediate anti-CD2 induced suppression of anti-CD3-driven interleukin-2 production and CD25 expression. 886 88

As shown previously, native or recombinant (r) human platelet factor 4 (PF4) alleviates the suppression induced by Con A or dimaprit, a histamine type 2 receptor (H2-R) agonist, in a murine system. The effect of rPF4 on human peripheral blood cells has now been studied, using as a model pokeweed mitogen (PWM)-induced, T-cell-mediated suppression of Ig-secreting cell (ISC) formation by Staphylococcus aureus and rIL-2 activated B cells. PWM, but not phytohemagglutinin (PHA), induced inhibitory activity in mitomycin-treated CD8+ T cells, but not unfractionated or CD4+ T cells, for both ISC formation and B cell proliferation. rPF4 and its C-terminal tridecapeptide alleviated the suppressive effect of PWM-activated CD8+ T cells on ISC production but not on proliferation. Heparin did not prevent this immunoregulatory activity of PF4. Neutralizing antibody to TGF-beta, but not to IFN-gamma or TNF-alpha, alleviated the suppression of ISC formation in some of the experiments. The H2-R appeared to play a part in inducing suppression, because the H2-R antagonist, cimetidine, prevented the PWM-induced suppression of ISC production. Furthermore, dimaprit induced suppression of ISC formation when added instead of PWM at the start of culture. Incubation of CD8+ T cells with dimaprit for only 3 hr prior to coculture with S. aureus + IL-2 activated B cells decreased the ISC response. This suppression was also alleviated by addition of rPF4 to the coculture. Similar to dimaprit, known cAMP upregulating agents, such as forskolin, dibutyryl cAMP, and cAMP analog, all induced this immunoregulatory activity in T cells. Moreover, the effect of dimaprit was prevented by the specific protein kinase A inhibitor, HA1004, suggesting strongly that upregulation of cAMP played a role in the H2-R-mediated effect. Cell contact appeared to be necessary, since supernatants from dimaprit or PWM activated T cells failed to suppress ISC production. We suggest that the known ability of PF4 to prevent TGF-beta-mediated effects on endothelial and other target cells may be involved in the alleviating effect of PF4 on the cell-contact-dependent CD8+ T-cell-mediated B cell suppression.
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PMID:Induction of inhibitory activity for B cell differentiation in human CD8 T cells with pokeweed mitogen, dimaprit, and cAMP upregulating agents: countersuppressive effect of platelet factor 4. 896 82


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