UNIPROT:P14784 - FACTA Search

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Query: UNIPROT:P14784 (IL-2 receptor)
3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects mediated by a combined stimulation of cAMP- and protein kinase C (PKC)-dependent pathways have been investigated in different cellular systems, and it has been shown that they may complement each other in activating cell proliferation and differentiation. In this report, we show that upon the stimulation of both pathways T lymphocytes became refractory to activation via the CD3/T cell receptor (TcR) complex. T cells preincubated with phorbol 12-myristate 13-acetate (PMA) and dibutyryl cAMP (Bt2cAMP) displayed a deficient proliferative ability in response to anti-CD3 mAb stimulation, whereas lymphocytes treated individually with either Bt2cAMP or PMA responded comparably to untreated samples. We detected an association between the reduced mitogenic response and low expression of both interleukin-2 (IL-2) and the alpha chain (CD25) of the IL-2 receptor (IL-2R). Analysis of intracellular Ca2+ mobilization suggested that the CD3/TcR-dependent signal transduction was impaired in PMA/Bt2cAMP-treated cells. Remarkably, we observed that these samples displayed a persistent expression of the c-fos protooncogene, associated to an increased AP-1 DNA-binding activity, whereas no variations of CREB or NF-kB were detected. Neither Bt2cAMP nor PMA individually mediated these sustained effects, which therefore appear as a consequence of the interplay between both metabolic stimuli. Altogether, the data provide the evidence that both pathways complement each other in regulating gene expression and, conversely, downregulate the TcR transduction mechanisms.
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PMID:Costimulation of cAMP and protein kinase C pathways inhibits the CD3-dependent T cell activation and leads to a persistent expression of the AP-1 transcription factor. 839 37

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

Activation of T cells results in a cascade of gene activation and subsequent proliferation and differentiation into effector phenotypes. The regulation of transcription factors belonging to the signal transducer and activator of transcription (STAT) family was analyzed in PHA-activated mononuclear cells and in purified T cells activated by cross-linking cell surface CD3. Cell activation resulted in a delayed induction of STAT DNA-binding activity, which was sustained for several days, was composed predominantly of Stat1 and Stat3, and was blocked by cycloheximide and actinomycin D. Increased Stat1 and Stat3 mRNA and protein levels were detected, respectively 4 and 24 h after activation. Stimulation of the cAMP signal transduction pathway, which skews cytokine production toward a Th2 pattern, resulted in the preferential suppression of Stat1 activity. cAMP inhibited the induction of expression of IL-2 receptor components, but did not inhibit IL-4 receptor alpha-chain and CD69 expression or the induction of activator protein 1 transcription factors. cAMP signaling inhibited Stat1 at several different levels, including suppression of DNA binding and down-regulation of Stat1 protein and mRNA levels. Our results demonstrate the regulation of STAT activity by a signaling pathway that regulates the T cell functional phenotype and is distinct from the cytokine-activated Janus kinase-STAT signaling pathway.
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PMID:Inhibition of transcription factor Stat1 activity in mononuclear cell cultures and T cells by the cyclic AMP signaling pathway. 875 21

Using methods of fluorescence flow cytometry and Western blot analysis, Rg1 was found to enhance the expression of IL-2 receptor alpha chain and inhibit the release of soluble IL-2 receptor. In in vitro experiment, Rg1 showed no influence on Con A-induced increase of cytoplasmic free calcium concentration, but significantly increased the levels of intracellular cAMP and cGMP in aged animals. In view of the important role of cAMP and cGMP as second messengers in the regulation of immune system, the results of the present studies suggest that one of the mechanisms by which Rg1 enhances immune function in old rats might be mediated by increase of cAMP and cGMP contents, resulting in IL-2 gene expression and splenocyte proliferation.
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PMID:[Studies on the mechanisms of immunoregulatory effects of ginsenoside Rg1 in aged rats]. 876 68

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

Activation and translocation of protein kinases C is a key event in the regulation of T lymphocyte activation, proliferation and function. Stimulation of human peripheral blood lymphocytes with the monoclonal antibody BMA 031 raised against the T cell antigen receptor led to a bimodal activation of protein kinases C. The immediate activation and translocation of the protein kinase C isoform PKC-alpha was followed by activation and translocation of the protein kinase C-beta isoenzyme after 90 min of stimulation. Pretreatment of the cells with cholera toxin for 90 min completely abolished activation of protein kinase C-alpha. In sharp contrast, activation and translocation of protein kinase C-beta was not influenced by the bacterial toxin, suggesting that activation and translocation of different protein kinase C isoenzymes are regulated by distinct mechanisms of transmembrane signalling coupled to the T cell antigen receptor/CD3 complex. The expression of high affinity IL-2 receptors was completely inhibited by cholera toxin, while IL-2 synthesis and secretion were not influenced in BMA 031-stimulated human lymphocytes. Extensive control experiments have shown that the effects of cholera toxin were not mediated by its B subunit, and were independent of elevation of intracellular cAMP concentration, suggesting that cholera toxin interfered with a signalling pathway leading to activation of protein kinase C-alpha, which could be responsible for the inhibition of IL-2 receptor expression. This hypothesis was substantiated by the finding that upon introduction of antibodies against protein kinase C-alpha, IL-2 receptor gene expression was completely suppressed. The results suggest, that protein kinase C-alpha might be the major protein kinase C isoenzyme of a signal transduction cascade regulating IL-2 receptor expression in stimulated human lymphocytes.
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PMID:T cell antigen receptor dependent signalling in human lymphocytes: cholera toxin inhibits interleukin-2 receptor expression but not interleukin-2 synthesis by preventing activation of a protein kinase C isotype, PKC-alpha. 915 Feb 81

Interleukin-4 (IL-4) regulates the expression of the 55-kDa alpha-subunit (CD25) of the IL-2 receptor complex in human B lymphocytes. This report suggests that the cAMP/protein kinase A (PKA) component of the IL-4 receptor signalling programme in human tonsillar B cells has a functionally important role in regulating expression of the CD25 gene by attenuating activity of a protein binding to a potent negative regulatory element (NRE) in the CD25 promoter; this effect can be mimicked by agents that elevate cAMP and blocked by inhibitors of PKA but not protein kinase C (PKC). In a B-cell line that fails to elevate cAMP, attenuate NRE-binding protein (NRE-BP) activity or express CD25 following IL-4 treatment, stimulation of cAMP accumulation by forskolin facilitates IL-4-mediated induction of both the endogenous gene and an exogenous reporter gene under the control of a minimal promoter/enhancer fragment of the CD25 gene.
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PMID:A functional role for interleukin (IL)-4-driven cyclic amp accumulation in human b lymphocytes. 1084 54

We investigated the effects of drugs, especially anti-pulmonary disease agents, on the production of cytokines from human peripheral blood mononuclear cells (PBMC). Roxithromycin (RXM), a macrolide antibiotic with the structure of 14-member macrocycline ring increased adherent cells (monocyte/macrophages), whereas it suppressed the proliferation of PBMC stimulated with phytohemagglutinin (PHA). RXM suppressed the production of IL-1 beta and TNF-alpha from lipopolysaccharide (LPS)-stimulated PBMC in a dose-dependent manner. Levofloxacin, a fluorinated quinolone, increased IL-2 production by PBMC stimulated with PHA. The production of GM-CSF and soluble IL-2 receptor was suppressed at high concentrations of LVFX. LVFX suppressed IL-1 beta production, but did not the production of TNF-alpha and IL-8 production. A beta-adrenoceptor agonists (beta-agonist), procaterol, clenbuterol, fenoterol and terbutaline suppressed the production of TNF- and IL-1 beta. TNF-alpha production was almost completely suppressed by dibutyryl cyclic AMP (dbcAMP), whereas IL-1 beta production appeared to be partially refractory even at the highest concentration examined. Both procaterol and theophylline elevated cAMP levels in LPS-stimulated PBMC, but the effect of procaterol was limited. The inhibition of the production of TNF-alpha and IL-1 beta by procaterol was additively potentiated with theophylline. Of examined phosphodiesterase (PDE) isozyme inhibitors type IV PDE inhibitors were more effective in inhibiting the production of TNF-alpha and IL-1 beta by LPS-stimulated PBMC than a nonselective, type III or type III/IV inhibitor. The addition of the beta-agonist increased the inhibitory effect of tested PDE inhibitors on the production of TNF-alpha and IL-1 beta Type IV, type III and nonselective PDE inhibitors were effective in inhibiting the production of IFN-gamma and IL-2 in a dose-dependent manner. In contrast, the production of IL-4 and IL-5 was inhibited by only the highest concentration of type IV inhibitor, and other agents had no effect on the production. Similarly, dbcAMP inhibited the production of IFN-gamma and IL-2 more potently than that of IL-4 and IL-5. The addition of the beta-agonist increased the inhibitory effect of tested PDE inhibitors on the production of IFN-gamma and IL-2 production. These findings indicate that these agents have an immunodulatory action on the production of cytokines by PBMC and also indicate that they could be potent pharmacological agents for the treatment of diseases in which several cytokines are important etiological factors.
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PMID:[Modulation of cytokine production from human mononuclear cells by several agents]. 1119 79

OBJECTIVE: To study molecular mechanism of suppressive effect of macrophages posttrauma on T cell functions. METHODS: A murine closed trauma model was used, macrophages were harvested from the abdominal cavity and added into the culture system of T cells, which were separated from splenocytes in normal mice using nylon column. T cell functions and intracellular messenger molecules were determined. In addition, the effect of macrophages' removal from splenocytes of traumatized mice on T cell functions and intracellular messenger molecules was investigated. RESULTS: Macrophages posttrauma in vitro could obviously suppress ConA stimulated normal T cell functions such as T lymphocyte transformation, interleukin 2 (IL-2) production, IL-2 receptor alpha (IL-2Ralpha) expression, IL-2 mRNA and IL-2Ralpha mRNA levels, and elevate cAMP contents of activated normal T cells while decreasing cGMP contents, intracellular free calcium ([Ca(2+)]i) concentration and protein kinase C (PKC) activity. Removal of macrophages from splenocytes of traumatized mice could at certain degree reverse the suppression of T cell functions, decrease cAMP contents while increasing cGMP contents, [Ca(2+)]i concentration and PKC activity. CONCLUSIONS: Macrophages posttrauma may suppress T cell functions via altering messenger molecule levels in activated T cells.
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PMID:The effect of macrophages posttrauma on T cell functions. 1187 49

DAB(389)IL-2 (ONTAK) is a fusion protein consisting of the ADP-ribosyltransferase and membrane translocating domains of native diphtheria toxin and the full-length sequence for interleukin-2 (IL-2) gene. In vitro data demonstrates that DAB(389)IL-2 is cytotoxic to cells expressing the high affinity IL-2 receptor (IL-2R). In Phases I and II clinical trials of patients whose tumor cells express a component of the IL-2R, the response rates were 18% for B-cell non-Hodgkin lymphoma (NHL) and 30% for cutaneous T-cell lymphoma (CTCL). In this study, we examined the effects of arginine butyrate on IL-2R expression and susceptibility of leukemia cells to intoxication by DAB(389)IL-2. We demonstrate that the p75 subunit of the IL-2R (IL-2Rbeta) is upregulated in the presence of low concentrations of arginine butyrate (0.06mM) which had no direct growth inhibitory effect on the cells. To explore mechanisms of this upregulation, we examined the effect of 0.06mM arginine butyrate on relevant transcriptional elements and on histone deacetylase and found activation of cAMP response element (CRE) but not NFAT or NFKB, as well as inhibition of histone deacetylase (HDAC). Our results suggest that the effects of physiologically achievable concentrations of butyrate on IL-2R expression could be exploited to enhance the susceptibility of intermediate and low-affinity IL-2R expressing leukemia cells to DAB(389)IL-2.
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PMID:Arginine butyrate increases the cytotoxicity of DAB(389)IL-2 in leukemia and lymphoma cells by upregulation of IL-2Rbeta gene. 1244 77

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