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

Data from a variety of sources suggest that one target cell for levamisole might be the macrophage. Current results reveal that oral levamisole pre-treatment provides elicited peritoneal macrophages with the ability to respond better to ex vivo LPS stimulation, and that levamisole can directly act on LPS-stimulated macrophages in vitro, resulting in enhanced production of IL-1, a key mediator of the immune response. These data offer further biological and immunologic evidence that IL-1 production is indeed enhanced by levamisole. Finally, these phenomena were not confined to macrophages taken from mice given levamisole. Increased IL-1 expression was found to occur for cells treated in vitro with levamisole, demonstrating that there were direct effects by levamisole on LPS-stimulated macrophage cytokine production. IL-1 has been reported to have a number of direct and indirect anti-tumor effects which might be sufficient to provide localized protection against tumor invasion or growth in the adjuvant setting. The findings described above are therefore consistent with suggestions of an increased host response in certain types of cancer due to levamisole treatment, and are also consistent with reports of levamisole's providing a beneficial effect in other cases of immunodeficiency disease. Recent clinical data provided by Janik et al. demonstrate that levamisole administration caused increases in circulating levels of neopterin and soluble IL-2 receptor (sIL-2R). This in vivo result is consistent with in vitro data showing augmented IL-1 induction after levamisole treatment, since neopterin is a marker for macrophage activation and sIL-2R release correlates with IL-2 production and binding after IL-1 activation of T-cells. These data are therefore consistent with the hypothesis that levamisole can induce a macrophage-derived cytokine cascade which may have beneficial effects in host responses to human cancer. It is attractive to speculate that there may be increased cytokine expression in vivo (yet to be confirmed) which might contribute to the added clinical benefit when 5-FU is combined with levamisole. Data from nude mice bearing human tumor xenografts demonstrate improved antitumor responses to 5-FU in combination with levamisole, and it will be interesting to determine whether increased interferon, TNF, or other cytokines can be observed in this model. In addition, the ability of levamisole to increase ICAM-1 expression on certain tumor cell lines may be a mechanism by which similar cells are rendered more sensitive to host effector mechanisms in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Experimental modulation of IL-1 production and cell surface molecule expression by levamisole. 810 13

Cytokine pathways are central to the perpetuation of synovial inflammation in rheumatoid arthritis (RA). Azathioprine (AZA) has disease modifying activity in RA. This study addressed the effect of AZA on serum IL-6 and soluble IL-2 receptor (sIL-2R) levels in RA. Over a 24 week period of therapy significant clinical improvement was observed. However, serum levels of both IL-6 and soluble IL-2R levels did not significantly change after AZA therapy. AZA therapy did not significantly alter the peripheral blood monocytes ability to produce IL-6 in vitro, either in the presence or absence of LPS. The mechanism by which AZA achieves clinical improvement in RA patients does not appear to be through IL-6 modulation or modification of synovial lymphocyte activation as assessed by serum sIL-2R levels.
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PMID:The effect of azathioprine on serum levels of interleukin 6 and soluble interleukin 2 receptor. 816 44

To examine the role of cellular interactions involving class I histocompatibility antigens in the response to low concentrations of phytohaemagglutinin, we studied the effect of antibodies to components of these antigens on proliferative responses, interleukin-1 and interleukin-2 production, and IL-2 receptor expression. Antibody to human beta 2-microglobulin (beta 2m) had an inhibitory effect both on IL-2 accumulation at 48 h of culture and on the proliferative response 24 h later. Exogenous IL-2 completely reconstituted the inhibited proliferative responses, and also restored the modest decrease in IL-2 receptor expression that was induced by anti-beta 2m. Pretreatment of either purified monocytes or T cells with anti-beta 2m had a similar inhibitory effect both on proliferation and on interleukin-2 production. By contrast, IL-1 production by LPS- or silica-stimulated monocytes was not affected by this antibody. Kinetic experiments demonstrated that anti-beta 2m was equally inhibitory when added at the initiation of culture or after 24h, and significant inhibition occurred when the antibody was added as late as 48 h. Our results are consistent with an ongoing role for class I antigens in the cellular interactions between lymphocytes and accessory cells required for the production of IL-2.
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PMID:Evidence for an ongoing role of class I histocompatibility molecules for the production of interleukin-2 in response to suboptimal concentrations of phytohaemagglutinin. 848 1

Natural killer (NK) cells are large granular lymphocytes that constitutively express functional IL-2 receptors. We have shown that recombinant human IL-15 uses the IL-2 receptor to activate human NK cells and can synergize with recombinant human IL-12 to stimulate NK cell production of IFN-gamma in vitro. IFN-gamma production by NK cells is critical in the prevention of overwhelming infection by obligate intracellular microbial pathogens in several experimental animal models. Herein, we demonstrate that human monocytes produce IL-15 protein within 5 h of activation with LPS. Using an IL-15-neutralizing antiserum in a coculture of LPS-activated monocytes and NK cells, we demonstrate that monocyte-derived IL-15 is critical for optimal NK cell production of IFN-gamma. Endogenous IL-15 activates NK cells through the IL-2 receptor, and with endogenous IL-12, regulates NK cell IFN-gamma after monocyte activation by LPS. These in vitro studies are the first to characterize a function for endogenous IL-15, and as such, suggest an important role for IL-15 during the innate immune response. IL-15 may be an important ligand for the NK cell IL-2 receptor in vivo.
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PMID:Endogenous production of interleukin 15 by activated human monocytes is critical for optimal production of interferon-gamma by natural killer cells in vitro. 867 21

Expression of the immunoglobulin J chain is initiated by lymphokine signals delivered to activated B cells during a primary immune response. In the mature murine B cell line, CH12.LX, IL-5 and LPS but not IL-2 were found to greatly enhance basal levels of J chain gene expression. Analysis of the IL-2 receptor (IL-2R) showed two defects: an unusually low expression of the IL-2R alpha chain and little or no IL-2R beta chain. Treatment with IL-5 strongly amplified IL-2R alpha chain expression in CH12.LX cells, yet failed to confer IL-2 responsiveness. However, when the IL-2R beta chain was introduced by stable transfection, the cells expressed 400-500 high affinity IL-2R and responded to IL-2 with increased J chain expression. Surprisingly, in the absence of exogenous lymphokine stimulation, the basal levels of J chain and IL-2R alpha in all IL-2R beta transfectants became significantly elevated over time. Analysis showed that CH12.LX cells constitutively synthesized IL-2 and, given a functional IL-2R, responded to the lymphokine in an autocrine fashion to upregulate both J chain and IL-2R alpha. Thus, CH12.LX cells provide a model cell line in which the role of the IL-2R beta chain in differentiative events such as J chain upregulation can be examined.
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PMID:Expression of the immunoglobulin J chain in a murine B lymphoma is driven by autocrine production of interleukin 2. 889 32

Head-Down Bed-Rest (HDBR) mimics some of the physiological stress effects of microgravity. Six healthy volunteers were subjected to bed-rest for 120 days. Blood samples were collected one month before (PRE), on day 110 of HDBR (DAY 110), and on the 7th day after bed-rest regime ends (POST). Distribution of T-cell subsets, NK-, B-cells and monocytes was assessed in the whole blood. Distribution of cytokine secreting T-cells was assessed in PMA/ionomycin cell culture. Peripheral Blood Mononuclear Cells (PBMC) and whole blood cells (WB) were activated with a combination of PHA and LPS to assess cytokine secretion. In addition, PHA/LPS activated cell cultures were treated with 10(-6) M of hydrocortisone (HCS) in order to study stress-induced alterations in the cortisol-sensitivity of immunocytes. Results from HCS culture were compared to non-treated control cultures. Stress factors of HDBR affect immune responsiveness and immune-endocrine homeostatic interrelations in vitro as follow: 1) alter expression of surface receptor to IL-2 (CD25) by CD4+ and CD8+ T-cell subsets in PHA/LPS activated PBMC culture; 2) alter distribution of IL-2 and/or IFN-gamma producing CD4+ and CD8+ T-cells in PMA/ionomycin activated culture; 3) significantly affect secretion of IL-2, IFN-gamma, and IL-4, but not IL-10 and soluble IL-2 receptor alpha in PHA/LPS activated PBMC culture; 4) shift Type 1 vs. Type 2 cytokine balance in PHA/LPS activated culture toward to Type 1 response; 5) in vitro treatment with hydrocortisone unequally modulate expression of CD25 on CD4+, and CD8+ T-cells, as well as secretion of Type 1 and Type 2 cytokines in PHA/LPS activated PBMC culture during bed-rest regime; 6) assessment of immune profile depends from the cellular and humoral milieu of cell culture.
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PMID:Type 1 vs. type 2 cytokine secretion in vitro and its regulation by hydrocortisone in humans subjected to 120-day anti-orthostatic bed-rest regime. 1463 61

IL-15 has been found to activate NF-kappaB in various types of cells. However, the role of this transcription factor in IL-15- and IL-21-stimulated murine bone marrow (BM) cells is unclear. In this study, we demonstrated that both IL-15 and IL-21 are capable of delaying BM cell factor deprivation-induced apoptosis, but only IL-15 induced their proliferation. Following separation of BM cells into myeloid (CD11b(+)) and lymphoid (CD11b(-)) cell populations, we found that IL-15, but not IL-21, significantly induced proliferation in both cell populations. Both cytokines significantly delayed apoptosis, but only in CD11b(-) BM cells. IL-15Ralpha, CD122 (IL-2/15Rbeta), and common gamma-chains (CD132) were expressed in both populations, whereas IL-21Ralpha was expressed only in CD11b(-) BM cells. In addition, we demonstrated that IL-15-induced BM cell proliferation was significantly inhibited in NF-kappaBp50(-/-) mice when compared with littermate controls. The ability of IL-15 and IL-21 to delay BM cell apoptosis was slightly inhibited in NF-kappaBp50(-/-) mice, whereas the antiapoptotic effect of LPS was markedly reversed. We conclude that IL-15, but not IL-21, induces BM cell proliferation and that both cytokines delay BM cell apoptosis. These biological activities were preferentially observed in CD11b(-) BM cells. Using NF-kappaBp50(-/-) mice, we demonstrated for the first time that NF-kappaB plays a greater role in IL-15-induced cell proliferation than in IL-15- and IL-21-induced suppression of apoptosis.
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PMID:Differential effects of IL-15 and IL-21 in myeloid (CD11b+) and lymphoid (CD11b-) bone marrow cells. 1678 4

Recently, attention has been focused on the role for dendritic cells (DCs) in the promotion of peripheral tolerance. It is currently believed that the maturation/activation state of DCs might be a control point for the induction of graft tolerance through modifications of the activation state of T cells. We have observed IL-2, and IL-2 receptor gene expression by reverse transcriptase-polymerase chain reaction (RT-PCR) in human DC lysates following bacterial stimulation. It has been demonstrated in the present study IL-2R alpha (CD25) expression on human DCs upon LPS activation. DCs differentiated from monocytes were exposed to anti CD25 during maturation, anti CD25 treatment affected the abilities of human DCs to induce CD4+ T cell proliferation in response to alloantigens, maintained endocytic capacity, Anti CD25 treated DCs produce low levels of IL-12 and IFN and high level of IL-10. All these characteristics suggest that DCs may be used in cellular therapy either to induce allograft tolerance (anti CD25 treated DCs) or to restore immunity against tumors (IL-2 treated DCs).
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PMID:Anti CD25 treatment of human dendritic cells modulates both their cytokine synthesis profiles and their capacity to activate allogeneic CD4 T cells: a potential tolerogenic effect. 1827 95

Murine gammaherpesvirus 68 (MHV68) establishes long-term latency in memory B cells similar to the human gammaherpesvirus Epstein Barr Virus (EBV). EBV encodes an interleukin-10 (IL-10) homolog and modulates cellular IL-10 expression; however, the role of IL-10 in the establishment and/or maintenance of chronic EBV infection remains unclear. Notably, MHV68 does not encode an IL-10 homolog, but virus infection has been shown to result in elevated serum IL-10 levels in wild-type mice, and IL-10 deficiency results in decreased establishment of virus latency. Here we show that a unique MHV68 latency-associated gene product, the M2 protein, is required for the elevated serum IL-10 levels observed at 2 weeks post-infection. Furthermore, M2 protein expression in primary murine B cells drives high level IL-10 expression along with increased secretion of IL-2, IL-6, and MIP-1alpha. M2 expression was also shown to significantly augment LPS driven survival and proliferation of primary murine B cells. The latter was dependent on IL-10 expression as demonstrated by the failure of IL10-/- B cells to proliferate in response to M2 protein expression and rescue of M2-associated proliferation by addition of recombinant murine IL-10. M2 protein expression in primary B cells also led to upregulated surface expression of the high affinity IL-2 receptor (CD25) and the activation marker GL7, along with down-regulated surface expression of B220, MHC II, and sIgD. The cells retained CD19 and sIgG expression, suggesting differentiation to a pre-plasma memory B cell phenotype. These observations are consistent with previous analyses of M2-null MHV68 mutants that have suggested a role for the M2 protein in expansion and differentiation of MHV68 latently infected B cells-perhaps facilitating the establishment of virus latency in memory B cells. Thus, while the M2 protein is unique to MHV68, analysis of M2 function has revealed an important role for IL-10 in MHV68 pathogenesis-identifying a strategy that appears to be conserved between at least EBV and MHV68.
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PMID:The MHV68 M2 protein drives IL-10 dependent B cell proliferation and differentiation. 1838 62

The persistent environmental toxicant and immunomodulator, lead (Pb), has been proposed to directly target CD4(+) T cells. However, our studies suggest that CD4(+) T cells are an important functional, yet indirect target. In order to identify the direct target of Pb in the immune system and the potential mechanism of Pb-induced immunotoxicity, myeloid suppressor cells (MSCs) were evaluated for their ability to modulate CD4(+) T cell proliferation after Pb exposure. Myeloid suppressor cells regulate the adaptive immune response, in part, by inhibiting the proliferation of CD4(+) T cells. It is thought that the mechanism of MSC-dependent regulation involves the release of the bioactive gas, nitric oxide (NO), blocking cell signaling cascades downstream of the IL-2 receptor and thus preventing T cells from entering cell-cycle. In mixed lymphocyte culture (MLC), increasing numbers of MSCs suppressed T cell proliferation in a dose-dependent manner, and this suppression is strikingly abrogated with 5 microM lead (Pb) treatment. The Pb-sensitive MSC population is CD11b(+), GR1(+)and CD11c(-) and thus phenotypically consistent with MSCs described in other literature. Inhibition of NO-synthase (NOS), the enzyme responsible for the production of NO, enhanced alloreactive T cell proliferation in MLC. Moreover, Pb attenuated NO production in MLC, and exogenous replacement of NO restored suppression in the presence of Pb. Significantly, MSC from iNOS-/- mice were unable to suppress T cell proliferation. An MSC-derived cell line (MSC-1) also suppressed T cell proliferation in MLC, and Pb disrupted this suppression by attenuating NO production. Additionally, Pb disrupted NO production in MSC-1 cells in response to treatment with interferon-gamma (IFN-gamma) and LPS or in response to concanavalin A-stimulated splenocytes. However, neither the abundance of protein nor levels of mRNA for the inducible isoform of NOS (iNOS) were altered with Pb treatment. Taken together these data suggest that Pb abrogates an MSC-dependent suppression of alloreactive T cell proliferation by inhibiting the function, but not the expression of iNOS.
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PMID:Reduction of myeloid suppressor cell derived nitric oxide provides a mechanistic basis of lead enhancement of alloreactive CD4(+) T cell proliferation. 1843 16


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