Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report here that interleukin 2 (IL-2) acts on human blood monocytes by enhancing binding activity of the transcription factor NF-kappa B to its consensus sequence in the 5' regulatory enhancer region of the IL-2 receptor alpha chain (p55). Similarly, IL-2 activates NF-kappa B in the human monocytic cell line U 937, but not in resting human T-cells. This effect is detectable within 15 min and peaks 1 h after exposure to IL-2. Enhanced NF-kappa B binding activity is followed by functional activation in that inducibility of the IL-2 receptor alpha chain is mediated by enhanced NF-kappa B binding and that a heterologous promoter containing the NF-kappa B consensus sequence (-291 to -245) of the IL-2 receptor alpha chain gene is activated. In addition, IL-2 is capable of increasing transcript levels of the p50 gene coding for the p50 subunit of the NF-kappa B transcription factor, whereas mRNA levels of the p65 NF-kappa B gene remained unchanged.
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PMID:Activation of NF-kappa B by interleukin 2 in human blood monocytes. 141 5

It is widely believed that calcium antagonists such as diltiazem exert immunosuppressive effects in kidney graft recipients--however, the mechanism is unclear. In a randomized controlled trial, kidney graft recipients who received diltiazem during transplantation and for an average of 12 months thereafter experienced significantly fewer rejection episodes than patients treated with cyclosporine and steroids alone. Furthermore, 1-year (97% vs. 85%) and 4-year (80% vs. 70%) graft survival rates were higher in diltiazem-treated patients, but the difference was not statistically significant. In vitro, diltiazem had little immunosuppressive activity. Concentrations of diltiazem which blocked the proliferation of PHA-stimulated human peripheral blood mononuclear cells, or prevented activation-associated accumulation of interleukin-2 mRNA, or p50- and p70-IL-2 receptor mRNA exceeded pharmacological concentrations by more than 100-fold. Both, CsA and high doses of diltiazem caused an increase of IL-6 mRNA. In contrast to these findings, the IL-6 plasma concentrations were comparable in both groups, whereas the serum concentration of soluble IL-2 receptors was decreased in patients treated with diltiazem. Administration of diltiazem caused an alteration of CsA metabolism. The whole-blood concentration of CsA metabolite 17 was significantly increased in diltiazem-treated patients, resulting in a five-times-higher concentration of this metabolite in the cellular blood compartment compared with the parent drug. Changes in metabolites 1, 8, and 18 levels were less pronounced. Although direct immunosuppressive properties of diltiazem are unlikely, diltiazem could support immunosuppression by altering CsA metabolism, and promoting accumulation of certain metabolites.
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PMID:Effects of diltiazem upon metabolism and immunosuppressive action of cyclosporine in kidney graft recipients. 187 1

Studies of NF-kappa B suggest that this enhancer binding activity corresponds to a family of at least four proteins (p50, p55, p75, and p85) differentially induced with biphasic kinetics during T cell activation. While p55 and p50 are closely related to the 50 kd DNA binding subunit of NF-kappa B, p75 and p85 exhibit DNA binding properties that distinguish them from this 50 kd polypeptide and its regulatory subunits I kappa B and p65. All four members of this kappa B-specific protein family are structurally related to the v-Rel oncoprotein and one, p85, appears identical to human c-Rel. v-Rel, but not nontransforming v-Rel mutants, binds to the kappa B enhancer and inhibits NF-kappa B-activated transcription from the IL-2 receptor alpha promoter and HIV-1 LTR. These findings suggest a Rel-related family of kappa B enhancer binding proteins and raise the possibility that the transforming activity of v-Rel is linked to its inhibitory action on cellular genes under NF-kappa B control.
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PMID:The v-rel oncogene encodes a kappa B enhancer binding protein that inhibits NF-kappa B function. 222 78

Stimulation of primary human T-lymphocytes via CD2 and CD28 adhesion molecules induces a long-lasting proliferation (> 3 weeks). This potent activation does not require accessory cells, such as monocytes, but depends on persistent interleukin 2 (IL-2) secretion and receptivity, which is associated with high and prolonged expression of the inducible CD25/IL-2 receptor alpha (IL-2R alpha) chain gene. The transcription factor NF-kappa B participates in the regulation of both IL-2 and IL-2R alpha genes, as well as multiple cellular genes involved in T-cell proliferation. To evaluate the role of NF-kappa B in human peripheral blood T-lymphocytes, we previously analyzed the activation of NF-kappa B-related complexes in response to CD2+CD28 costimulation. We demonstrated a long-term induction of p50/p65 heterodimer, a putative p65/c-Rel heterodimer, and a constitutive nuclear expression of KBF1/p50 homodimers. As the role of p50 remains unclear, we focused our present study on NF-kappa B1 (p50/p105) gene regulation. Using electrophoretic mobility shift assays and Western and Northern blot analyses, we studied NF-kappa B1 gene expression during T-cell stimulation via CD2+CD28. We observed a transient 4- to 5-fold increase of NF-kappa B1 gene expression at both the mRNA and protein levels, lasting for at least 24 h. p50 DNA-binding activity apparently stays highly controlled when p105 expression is enhanced by a physiological stimulus of peripheral blood T-cells. Partial inhibition of p50 and p105 expression by NF-kappa B1 antisense oligonucleotides significantly reduced T-cell proliferation and CD25/IL-2R alpha cell surface expression.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of NF-kappa B1 (p50/p105) gene expression in activation of human blood T-lymphocytes via CD2 and CD28 adhesion molecules. 790 83

The NF-kappa B/rel family of transcription factors regulates the expression of a number of genes, including interleukin 2 (IL-2), IL-2 receptor alpha chain (Tac), and others, controlling T lymphocyte activation. The CD28 antigen is involved in regulation of T cell activation. To investigate whether CD28 antigen regulates NF-kappa B factors, we analyzed the effect of an anti-CD28 monoclonal antibody (mAb), CLB-CD28/1, on the nuclear activity of NF-kappa B complexes in resting and CD3-activated peripheral blood mononuclear cells (PBMC) of 11 donors. Cells were incubated with or without the anti-CD3 mAb OKT3 and/or the mAb CLB- CD28/1. Then nuclear extracts were obtained and analyzed for their binding to a 32P-labeled oligonucleotide, corresponding to the NF-kappa B 5'-CAACGGCAGGGGAATCTCCCTCTCCTT-3' consensus sequence in electrophoretic mobility shift assays. PBMC incubated with control medium did not appear to contain significant levels of NF-kappa B nuclear activity. The anti-CD28 mAb did not induce any detectable NF-kappa B nuclear activity in PBMC when used alone, except for two cases. However, cells incubated with the anti-CD3 mAb displayed NF-kappa B nuclear activity in 7 of the 11 cases. The addition of anti-CD28 to the anti-CD3 mAb-stimulated cells enhanced the levels of NF-kappa B activity in eight PBMC, while it did not modify PBMC in one sample and partially inhibited the induction of NF-kappa B in the remaining two samples. The stimulatory effect of anti-CD28 mAb on NF-kappa B nuclear activity was detected also on CD3-stimulated purified T lymphocytes. By analysis with antisera recognizing the p50 and p65 components of the NF-kappa B/rel family, NF-kappa B complexes of CD3+CD28-stimulated PBMC were found to contain both p50 and p65 proteins. An enhanced production of IL-2 was detected in cultures of CD3+CD28-stimulated PBMC. Our results indicate that CD28 triggering can modulate the activity on NF-kappa B nuclear complexes in T lymphocytes stimulated via CD3. Such an effect appeared not to require the presence of accessory cells (AC) or AC-derived cytokines.
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PMID:Regulation of NF-kappa B nuclear activity in peripheral blood mononuclear cells: role of CD28 antigen. 802 54

The cascade of events within the first few minutes of T cell stimulation has been well characterized. Although many second messengers have been shown to be necessary and sufficient for T cell activation in a number of model systems, the rate-limiting step in peripheral T cells has not been demonstrated. To model effective versus ineffective CD3-mediated stimulation in peripheral T cells, we used two anti-CD3 mAbs that differ in their ability to stimulate purified T cells: OKT3, which causes early second messenger generation but is unable to activate T cells without a second signal, and 64.1, which stimulates T cell proliferation on its own. We found that tyrosine kinase activity was similar for both mAbs over a period of hours. However, the inositol phosphate response was stronger for 64.1 than for OKT3. To tie these events to gene activation, we measured NF-kappa B and NF-AT activity in the nucleus after anti-CD3 stimulation. Both stimuli induced the appearance of the NF-kappa B components (c-Rel, p65 (RelA), and p50 (NF-kappa B1)) and NF-kappa B DNA binding activity in the nucleus. However, only 64.1 induced NF-AT in the nucleus, correlating with its ability to activate T cells. Thus, NF-AT induction and IL-2 secretion were correlated with the levels of inositol phosphate release but not with gross levels of tyrosine kinase activity induced late following the response. On the other hand, NF-kappa B induction and IL-2 receptor expression occurred even with the smaller second messenger response generated by OKT3.
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PMID:Long-term inositol phosphate release, but not tyrosine kinase activity, correlates with IL-2 secretion and NF-AT induction in anti-CD3-activated peripheral human T lymphocytes. 803 43

Stimulation of highly purified human T-cells via CD2 and CD28 adhesion molecules induces and maintains proliferation for more than 3 weeks. This potent interleukin 2 (IL-2)-dependent activation does not require monocytes or accessory cells. Long-lasting IL-2 receptivity is associated with high-level expression of the inducible IL-2 receptor alpha chain (IL-2R alpha) gene that is regulated at both transcriptional and posttranscriptional levels. Increase of IL-2R alpha gene transcription involves the enhanced binding of the transcription factor NF-kappa B to its consensus sequence in the 5'-regulatory region of the IL-2R alpha gene. To dissect the molecular basis for the unusually persistent transcription of the IL-2R alpha gene, we analyzed nuclear NF-kappa B binding to a radiolabeled IL-2R alpha kappa B-specific oligonucleotide probe during the time course of CD2 + CD28 activation. Resting T-cell nuclear extracts contained KBF1/p50 homodimer. After stimulation, two new kappa B-specific complexes were identified as NF-kappa B p50-p65 heterodimer and putative c-Rel homodimer or c-Rel-p65 heterodimer. Both inducible complexes persisted for at least 3 weeks. Their relative levels were very similar for the duration of proliferation. In parallel, CD2 + CD28 activation triggered a significant intracellular thiol decrease, suggesting that oxygen radicals are involved in the signaling pathway of adhesion molecules. Finally, micromolar amounts of pyrrolidine dithiocarbamate, an oxygen radical scavenger that efficiently blocked the nuclear appearance of NF-kappa B in T-lymphocytes, also inhibited IL-2 secretion, IL-2R alpha cell surface expression, and T-cell proliferation. Together, these results suggest that NF-kappa B plays an important role in long-term activation of human primary T-lymphocytes via CD2 + CD28.
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PMID:Activation of primary human T-lymphocytes through CD2 plus CD28 adhesion molecules induces long-term nuclear expression of NF-kappa B. 809 18

Members of the NF-kappa B/Rel family of transcription factors are involved in the transcriptional regulation of numerous polypeptides important to the immune response and cellular growth. Several genes regulated in part by NF-kappa B/Rel such as interleukin 2, IL-2 receptor alpha, and GM-CSF are trans-activated via an indirect association with the HTLV-I Tax protein in virus-infected and transformed T cells. In this study, we have investigated the interactions between Tax and NF-kappa B/Rel in an attempt to elucidate the mechanism of Tax mediated trans-activation and its role in leukemogenesis. Transfection studies were performed in Jurkat T cells using expression vectors for individual NF-kappa B subunits and the Tax protein as well as an NF-kappa B regulated reporter plasmid. NF-kappa B proteins differentially trans-activated the HIV-1 enhancer-CAT reporter; co-expression of Tax abrogated the inhibitory effect of I kappa B alpha and a trans-dominant negative mutant of p65 (p65 delta), indicating that Tax was a trans-dominant activator of NF-kappa B-regulated genes. Co-immunoprecipitation studies with extracts from transfected cells and NF-kappa B and Tax subunit specific antibodies revealed that Tax did not co-immunoprecipitate with p50/p105, c-Rel, or I kappa B; however, antibody specific to p65 was able to co-immunoprecipitate a 40kDa protein from Tax-transfected cells. Previous studies have demonstrated a physical interaction between Tax protein and p100, indicating that Tax may preferentially associate with specific NF-kappa B proteins.
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PMID:Interactions between HTLV-I Tax and NF-kappa B/Rel proteins in T cells. 815 9

Nuclear factor kappa B (NF-kappa B) has been shown to be an important transcriptional regulatory protein in multiple cell types in response to a number of physiological signals. In lymphocytes it has been implicated in transcriptional regulation of the kappa light chain, MHC, IL-6, and IL-2 receptor genes, depending on the differentiation state of the cell. In the present study we demonstrate that platelet-activating factor (PAF), a phospholipid molecule, activates NF-kappa B and increases kappa light chain mRNA in a human B cell line. Treatment of Ramos cells with PAF (10(-9) to 10(-6) M) increased RNA levels of the NF-kappa B p50 precursor, known as p105, in a dose-dependent manner. p105 RNA levels increased to a maximum observed at 8-10 hr and then diminished by 24 hr; this induction was not blocked by cycloheximide (CHX). PAF induced nuclear kappa B binding at similar concentrations, but more rapidly, attaining maximal levels within 15 min. CHX did not block this activity either. PAF treatment of Ramos cells also resulted in increased levels of RNA for kappa light chain. These results suggest that PAF activates NF-kappa B by at least two mechanisms in these cells, one at the level of post-translational protein activation and the other by increasing the level of RNA for NF-kappa B p105.
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PMID:Activation of NF-kappa B and immunoglobulin expression in response to platelet-activating factor in a human B cell line. 818 Oct 66

According to the widely accepted classification, human TH cell clones can be divided into two mutually exclusive subsets, TH1 and TH2, based on their profile of cytokine production. The intracellular difference between these clones is not clear. To characterize the biochemical nature of T-cell receptor (TCR)/CD3 complex-mediated signal transduction pathways, we introduced several human TH cell clones of THO- or TH1-like phenotype and analyzed the effects of various drugs and antibodies on cytokine production or proliferation of these clones. The tyrosine kinase inhibitor herbimycin inhibited the production of interferon-gamma (IFN-gamma) by THO-like clone, after stimulation with anti-CD3 monoclonal antibody alpha CD3-mAb) or with phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore A23187. However, whereas herbimycin strongly inhibited the production of IL-4 and IL-5 by alpha CD3 mAb stimulated T cells, it did not affect the production of these cytokines after PMA/A23187 stimulation. Cyclosporin A inhibited the proliferation as well as the production of the cytokines, including that of IL-2, IL-4, IL-5, and IFN-gamma, irrespective of the mode of stimulation. A23187, which synergizes with PMA in the induction of IL-4 and IFN-gamma, inhibited PMA-induced IL-10 production in a dose-dependent manner. Transforming growth factor-beta and anti-IL-2 receptor monoclonal antibody partially inhibited alpha CD3 mAb-mediated T-cell proliferation, but had no effect on the proliferation induced by PMA and A23187. Cyclic adenosine monophosphate (cAMP)-elevating drugs, like prostaglandin E2 and dibutyryl cAMP, inhibited the TCR-mediated cytokine production but shifted the cytokine production profile from a TH0 to a TH2 type after stimulation with PMA and A23187. Finally, we analyzed the induction of activity of two transcription factors, nuclear factor-kappa B (NF-kappa B) and nuclear factor of activated T cells, involved in the regulation of cytokine gene expression, after a different mode of activation. The induction of NF-kappa B (p50/p65 heterodimer) by using alpha CD3-mAb stimulation but not by using PMA/A23187 stimulation was found to be inhibited by using cAMP-elevating drugs.
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PMID:Factors affecting the cytokine production of human T cells stimulated by different modes of activation. 897 24


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