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)

Currently, the standard immunosuppressive regimen in organ transplantation is centred around cyclosporin. However, despite the use of this drug, rejection is not uncommon and it is associated with significant side-effects. Novel drugs and regimens have been developed to combat allograft rejection. Although FK506 has a similar mode of action and toxicity profile to cyclosporin, results, particularly in the rescue situation, have been encouraging. Sodium brequinar and rapamycin inhibit lymphocyte proliferation and may be most effective when used in combination with cyclosporin. Mycophenolate mofetil has been used in the treatment of psoriasis for many years; it is safe and will perhaps be useful in second-line therapy in patients unable to tolerate cyclosporin. The specific drugs highlighted in this chapter, although successful to differing degrees in preventing immunological rejection of allografts, have wide-ranging toxic effects on other organs in the body. Future use of these drugs is likely to utilize lower doses, supplemented by specific monoclonal antibody therapy, which can target diverse arms of the immune response. Large clinical trials using monoclonal antibodies against the T-cell receptor, the IL-2 receptor, CD4 T cells and specific adhesion molecules such as ICAM-1 are eagerly awaited. The number of new drugs and their mechanism of action, together with the widening spectrum of monoclonal antibodies available, will ensure that the next decade will be an exciting and hopefully profitable period in transplantation medicine. It is hoped that the introduction and assessment of these new agents will be rather more systematic and objective than that of their antecedents.
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PMID:New immunosuppressive treatment in transplantation medicine. 800 93

The effects of interleukin-2 (IL-2) on muscular Na+ currents were studied in human myoballs. The transient Na+ inward currents, elicited by repetitive depolarizations at 1 Hz and recorded in the whole-cell mode, were inhibited by the cytokine, the half-maximum effect occurring at about 500 U/ml. The effects resembled those of local anaesthetics without use dependence, as the inactivation (h infinity) curve was shifted in a negative direction while the current/voltage curve was not affected. As with these local anaesthetics, depolarization at 1, 4 and 8 Hz in the presence of IL-2 did not produce any cumulative block. The interaction of IL-2 with the Na+ channels is very fast (within ms) and it is suggested that it occurs when the Na+ channels are in the state of fast inactivation. The recovery from inactivation was only slightly slowed by IL-2, in agreement with the absence of any use dependence. All effects were readily reversible on washout of the cytokine. The effects were seen both in tetrodotoxin-(TTX)-sensitive adult Na+ channels and in TTX-insensitive juvenile channels. In contrast to the whole-cell configuration, no inhibition was visible in the attached-patch configuration. Further, the preincubation with an anti-IL-2-receptor antibody did not prevent the inhibitory effect of IL-2 on the Na+ currents. It is concluded that the cytokine blocks the voltage-dependent muscular Na+ channels by keeping the channels in the state of fast inactivation. An IL-2 receptor and a second messenger system are not likely to be involved in this reaction.
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PMID:Local anaesthetic-like effect of interleukin-2 on muscular Na+ channels: no evidence for involvement of the IL-2 receptor. 814 27

The role of the Legionella pneumophila protease in the pathogenesis of Legionnaires' disease is unclear. In this study, we assessed the effect of purified protease preparations on human recombinant interleukin-2 (IL-2), the IL-2 receptor, and several additional human T-cell surface proteins to determine whether protease contributes to the virulence of L. pneumophila by interfering with human T-cell activation and function. IL-2-induced proliferation of CTLL-2 cells was inhibited by coincubation with protease (10 to 100 U/ml). Protease at concentrations of > or = 10 U/ml cleaved human recombinant IL-2 as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of reaction mixtures containing 125I-labeled IL-2 and protease. Protease treatment of activated human T cells did not inhibit binding of a monoclonal antibody directed against the alpha subunit of the IL-2 receptor and did not interfere with binding of IL-2 to IL-2 receptors on the lymphocytes. Treatment of blood mononuclear cells or activated T cells with protease (50 U/ml) inhibited the binding of a monoclonal antibody directed against CD4. In contrast, protease treatment did not inhibit the binding of antibodies against CD3, CD8, class II major histocompatibility complex, and the transferrin receptor. Heat inactivation (65 degrees C for 20 min) of the protease or treatment with the metal chelator EDTA ablated the inhibitory effect of the protease. The ability of the protease to degrade IL-2 and cleave CD4 on human T cells suggests that protease may contribute to the pathogenesis of Legionnaires' disease by impeding T-cell activation and immune function.
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PMID:Legionella pneumophila protease inactivates interleukin-2 and cleaves CD4 on human T cells. 833 71

We have developed an enzyme-linked immunosorbent assay (ELISA) approach for the study of interactions between cytokines and glycosaminoglycans. This involves, as solid phase, a synthetic heparin-bovine serum albumin (BSA) complex in which the heparin is coupled via its reducing terminus to the protein using sodium cyanoborohydride. We have investigated the sensitivity and specificity of this experimental technique, employing antithrombin (AT III) and fibroblast growth factor 2 (FGF-2) as well-characterized heparin binding proteins. Using this ELISA method, we have established that human recombinant interleukin (IL-2) binds to heparin in a concentration-dependent manner. Soluble heparin competes for the binding of IL-2 to the complex with 50% inhibition at 5 microg/ml. This IC50 value provides an estimate of the binding constant of around 0.5 microM. This value is at least two orders of magnitude larger than that for the binding of IL-2 to its dimeric and trimeric cell surface receptors, but similar to that for binding to the IL-2 receptor beta polypeptide acting alone. Our ELISA shows that in addition to soluble heparin, fuciodan also competes for IL-2 binding, but chondroitin sulfate and dermatan sulfate are inactive. Of six heparan sulfates tested, only one highly sulfated preparation competed for IL-2. The interaction between IL-2 and heparin-like glycosaminoglycans is likely to be an important mechanism for retaining IL-2 close to its sites of secretion, thus giving rise to localized concentration gradients in the tissues.
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PMID:Characterization of human recombinant interleukin 2 binding to heparin and heparan sulfate using an ELISA approach. 941 13

Previously we found that sodium butyrate (NaBu) markedly enhanced production of the antibody specific for a T-cell-dependent antigen, sheep red blood cells (SRBC) in murine splenocytes (Kishiro, Y., Ueda, K., Fujiwara, M. and Yamamoto, I., Jpn J. Phamacol., 1994 66, 369-376. To gain a better understanding of the target cells for NaBu's action on antibody responses, we have utilized the T-cell-independent antigen, trinitrophenyl-lypopolysaccharide (TNP-LPS) as a stimulant and have examined an effect of NaBu on the anti-TNP antibody production in vitro. NaBu markedly increased the anti-TNP plaque-forming cell (PFC) responses in murine whole splenocytes, but not in murine splenic B cells. Addition of T-cells or the concanavalin A supernatant (CAS) from murine splenocytes to the B cell cultures completely restored the enhancing effect of NaBu. This effect of CAS was totally blocked by an anti-interleukin (IL)-2 antibody and partially by an anti-IL-1 beta or anti-IL-4 antibody. The full enhancing effect of NaBu was also detected when IL-2 was added to the B cell cultures, while IL-2 alone had no stimulatory effect on the control PFC response. IL-1 beta alone significantly stimulated the antibody production and adding NaBu to this IL-1 beta-supplemented culture caused a further increase. Neither IL-4 alone nor NaBu plus IL-4 had any effect on the PFC response. NaBu did not affect the expression of the IL-2 receptor alpha- and beta-chains in B cells stimulated with TNP-LPS. These results suggest that NaBu is an agent that promotes B cell differentiation in vitro in an IL-2-dependent manner.
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PMID:Interleukin-2-dependent augmentation of the anti-TNP antibody production by sodium butyrate in cultured murine splenic B cells. 946 54

Immunosuppression as a consequence of acute and chronic stress can increase the susceptibility of cattle to a range of infectious diseases. In order to develop a panel of immune function assays for investigating the effects of potential stressors on immune competence in cattle, the effect of treatment with short- and long-acting preparations of the synthetic glucocorticoid dexamethasone was examined. Short-acting dexamethasone (dexamethasone sodium phosphate 0.08 mg/kg) followed 37 h later by long-acting dexamethasone (dexamethasone-21 isonicotinate 0.25 mg/kg) was injected intramuscularly and blood was collected to assess immune functions at intervals over the subsequent 11 days from 6 treated and 6 control Hereford steers. Dexamethasone induced leukocytosis (neutrophilia, eosinopenia, lymphopenia, monocytosis), an increased neutrophil:lymphocyte ratio, an elevated percentage of CD4+ lymphocytes, a decreased total CD8+ lymphocyte count, decreased total and percentage WC1+ lymphocytes, an elevated percentage of IL-2 receptor alpha (IL-2Ralpha)+ lymphocytes, and an elevated percentage of B lymphocytes. In vitro chemotaxis of peripheral blood neutrophils to human C5a and ovine IL-8 was increased by dexamethasone treatment. Lymphocyte proliferation in the presence of phytohaemagglutinin, and serum concentrations of IgM, but not IgA or IgG1, were suppressed by dexamethasone treatment, whereas mitogen-induced production of interferon-gamma (IFN-gamma), neutrophil expression of CD18, neutrophil myeloperoxidase activity and natural killer (NK) cell activity were not influenced by dexamethasone treatment. The results indicate the potential for haematology and immune function assays to reflect elevated activity of the hypothalamic-pituitary-adrenocortical axis in cattle. Immunological parameters may thus provide a useful adjunct to cortisol and behavioural observations for assessing the impact of stress on the welfare of cattle.
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PMID:The effect of dexamethasone on some immunological parameters in cattle. 1059 72

Histone deacetylase (HDAC) inhibitors can induce transcriptional activation of a number of genes and induce cellular differentiation as histone acetylation levels increase. Although these inhibitors induce apoptosis in several cell lines, the precise mechanism by which they do so remains obscure. This study shows that HDAC inhibitors, sodium butyrate and trichostatin A (TSA), abrogate interleukin (IL)-2-mediated gene expression in IL-2-dependent cells. The HDAC inhibitors readily induced apoptosis in IL-2-dependent ILT-Mat cells and BAF-B03 transfectants expressing the IL-2 receptor betac chain, whereas they induced far less apoptosis in cytokine-independent K562 cells. However, these inhibitors similarly increased acetylation levels of histones in both cells. Although histone hyperacetylation is believed to lead to transcriptional activation, the results showed an abrogation of IL-2-mediated induction of c-myc, bag-1, and LC-PTP gene expression. This observed abrogation of gene expression occurred prior to phosphatidylserine externalization, a process that occurs in early apoptotic cells. Considering the biologic role played by IL-2-mediated gene expression in cell survival, these data suggest that its abrogation may contribute to the apoptotic process induced by HDAC inhibitors. (Blood. 2000;96:1490-1495)
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PMID:Histone deacetylase inhibitors suppress IL-2-mediated gene expression prior to induction of apoptosis. 1094 96

We studied the effects of the immunosuppressant sodium fusidate (fusidin) on murine immunoinflammatory diabetes mellitus (DM) induced by multiple low doses of streptozotocin (SZ). Fusidin was given by gavage to three strains of mice (C57KsJ, C57BL/6, CD1) at doses 10 or 100 mg/kg body weight every other day. The drug was administered as an early or late prophylactic regime starting either 1 day prior to the first or after the fifth and last injection of SZ. In both situations the largest dose of fusidin successfully reduced the clinical, chemical and histological signs of DM, the treated mice having significantly lower glycaemic values and milder (often absent) insulitis compared with sham-treated animals or controls given SZ alone. The antidiabetogenic effect was long-lasting as it was maintained up to 1 month after cessation of therapy. In contrast, fusidin prophylaxis failed to prevent development of hyperglycaemia acutely induced by one single and high (160 mg/kg) dose of SZ, which is a model of DM primarily due to the toxic action of SZ on the beta cells and does not involve immunopathogenetic mechanisms. On day 14 after SZ, fusidin markedly altered the circulating cytokine profile induced in vivo by ConA, reducing the levels of IFN-gamma, IL-2 and TNF-alpha and augmenting the level of IL-6. However, only the inhibitory effect of the drug on the synthesis/release of IFN-gamma seemed to be causally related to its capacity to counteract the SZ-induced DM. In fact, the disease was prevented by a neutralizing monoclonal antibody (mAb) against IFN-gamma, but not by anti-IL-2 receptor mAb, a soluble form of TNF-receptor type 1 or recombinant human IL-6. The prevention of disease by fusidin was also partly reversed by exogenously administered recombinant mouse IFN-gamma. The data provide further in-vivo evidence for the anti-diabetogenic and immunomodulatory properties of fusidin and indicate that this drug could have a role in prevention and treatment of human type 1 DM.
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PMID:Sodium fusidate ameliorates the course of diabetes induced in mice by multiple low doses of streptozotocin. 1109 Feb 38

Pathogenic lymphocytes in the enteric wall of inflammatory bowel disease patients display various abnormalities, including reduced sensitivity to apoptosis. We evaluated a therapeutic approach to elimination of cytotoxic cells, using two IL-2 fusion proteins, a diphtheria toxin (IL2-DT) and a caspase-3 (IL2-cas) conjugate. In models of acute (dextran sodium sulfate and trinitrobenzene sulfonic acid) and chronic (dextran sodium sulfate) toxic colitis, therapeutic doses of the fusion proteins improved survival and prevented colon shortening. While both chimeric proteins eradicated CD4(+)CD25(+)Foxp3(+) T cells in mesenteric LN, IL2-DT caused severe lymphopenia. In contrast, IL2-cas was equally protective and increased fractional expression of Foxp3. Similar effects of the fusion proteins were observed in healthy mice: IL2-DT caused lymphopenia and IL2-cas increased fractional expression of FoxP3. The fusion proteins induced apoptosis in CD25(+) T cells in vitro, with lower toxicity of IL2-cas to Foxp3(+) T cells. These data infer that targeted depletion of cells expressing the IL-2 receptor has therapeutic potential in models of inflammatory colitis, despite depletion of CD25(+) Treg. The IL2-cas fusion protein is particularly relevant to inflammatory bowel disease, as direct internalization of toxic moieties overcomes multiple pathways of resistance to apoptosis of colitogenic T cells.
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PMID:Targeted therapy to the IL-2R using diphtheria toxin and caspase-3 fusion proteins modulates Treg and ameliorates inflammatory colitis. 1973 74

Ganoderma sinensis fungal immunomodulatory protein (FIP-gsi) was a new member of FIPs family. Based on the cloning of FIP-gsi gene from G. sinensis, this paper reported that FIP-gsi gene was expressed in Escherichia coli expression system. Then, the recombinant proteins were analyzed by the sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). Finally, the immunomodulatory activity was examined by inducing cytokine genes expression. The results showed that the recombinant FIP-gsi protein could be expressed in E. coli and got the yield of about 25% of the soluble form in the total soluble protein. The FIP-gsi protein was composed of 111 amino acids, and the sequence of homologous rate was 88.6% with FIP-glu (LZ-8). Furthermore, it could enhance the levels of interleukin (IL)-2, IL-3, IL-4, interferon gamma, tumor necrosis factor alpha, and IL-2 receptor (IL-2R) in mouse spleen cells.
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PMID:Cytokines expression induced by Ganoderma sinensis fungal immunomodulatory proteins (FIP-gsi) in mouse spleen cells. 2017 87


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