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)

Injection of a low dose of mercuric chloride into Brown Norway (BN) rats caused a marked decrease in the concanavalin A (ConA)-induced generation of interferon-gamma-producing cells (IFN-gamma pc) in spleen cell cultures prepared 1 h after mercury administration. A second injection 48 h later caused a further diminution of IFN-gamma pc down to 30% of the number generated in splenocyte cultures of phosphate-buffered saline (PBS)-injected controls. Injection of Lewis rats with either one or two doses of HgCl2 revealed no inhibitory effect on splenic IFN-gamma production. The presence of the reduced form of glutathione (GSH) in the culture medium was found to be essential in these experiments. In the absence of GSH there was an overall 20-fold reduction of the number of IFN-gamma pc in splenocyte cultures of normal or PBS-injected rats, which was further reduced to a 60- to 70-fold-lower level in cultures of rats exposed to HgCl2. This mercury-mediated extra reduction could be fully reversed with an excess (2 mM) of GSH in Lewis but not in BN splenocyte cultures. Since the bivalent Hg2+ ion is known to bind to and inactivate sulfhydryl groups of proteins and low molecular weight thiols, most notably GSH, we investigated a possible role for thiols in IFN-gamma production. It was found that the generation of IFN-gamma pc in normal BN and Lewis splenocyte cultures was strongly dependent on GSH or its precursor cysteine in the culture medium. Other thiol compounds were also effective but disulfides were completely inactive. Depletion of intracellular GSH in ConA-stimulated splenocytes by buthionine sulfoximide (BSO), an inhibitor of de novo GSH biosynthesis, strongly inhibited the generation of IFN-gamma pc. The inhibitory effect of BSO was not abolished by the addition of interleukin-2 (IL-2), but was mimicked with antibodies directed to the IL-2 receptor. The data stress the importance of GSH in the enhancement of IL-2-mediated IFN-gamma production and are most consistent with a model in which mercury interferes with T cell IFN-gamma production by affecting the intracellular availability of GSH. The strain-specific susceptibility to mercury-mediated inhibition of IFN-gamma production is discussed.
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PMID:Mercuric chloride down-regulates T cell interferon-gamma production in brown Norway but not in Lewis rats; role of glutathione. 844 15

We have studied the expression of IFN-gamma, IL-2 and IL-2 receptor (IL-2R) at the mRNA and protein levels in spleen and lymph node cells from Trypanosoma cruzi-infected BALB/c mice. At 21 days post infection (dpi) (peak of parasitaemia), spleen cells stimulated with Con A for 16 h showed a reduced IFN-gamma, IL-2 and IL-2R mRNA production compared with non-infected controls. Lymph node cells obtained at 4, 21 or 60 dpi produced similar amounts of IFN-gamma, IL-2 or IL-2R transcripts after mitogen stimulation as uninfected controls. Spleen cells obtained at 21 dpi showed a lower Con A proliferative response and IL-2R expression compared with non-infected controls, while the proliferation and IL-2R expression of lymph node cells at 21 dpi was unaltered. Supernatants from 48 h Con A-stimulated spleen and lymph node cells from mice at 21 dpi had very low levels of IL-2 but contained significantly higher levels of IFN-gamma compared with the supernatants of cells from non-infected mice. The latter phenomenon correlates with an accelerated rate of IFN-gamma mRNA accumulation.
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PMID:Organ-specific regulation of interferon-gamma, interleukin-2 and interleukin-2 receptor during murine infection with Trypanosoma cruzi. 848 2

Immunization with live measles virus vaccine produces transient depression of delayed-type hypersensitivity (DTH) skin test responses and mitogen-induced lymphoproliferation irrespective of the serostatus of the recipient of the vaccine. To investigate this immune suppression further we studied peripheral blood mononuclear cells (PBMC) from adults before (N = 17) and at various times after (N = 34) immunization with measles virus vaccine. PHA-induced lymphoproliferation was decreased after vaccine and this was partly reversed by supplementation with rIL-2. There was no change in the proportion of PBMC that were CD4+ T cells, CD8+ T cells, NK cells, or B cells as analyzed by flow cytometry. Supernatant fluids were collected from PBMC after 72 hr in culture. Analysis for cytokines after vaccination showed spontaneous production of high levels of IL-4 (vaccinees 99 +/- 23; controls 5.6 +/- 5.6 ng/ml, P = 0.031) and TNF alpha (vaccinees 140 +/- 45; controls 42 +/- 14 pg/ml, P = 0.072) accompanied by low levels of IFN-gamma (vaccinees 1.3 +/- 0.6; controls 14.3 +/- 10.1 U/ml), IL-1 alpha (vaccinees 111 +/- 22; controls 442 +/- 107 pg/ml, P = 0.0001), and PGE2 (vaccinees 75 +/- 39; controls 300 +/- 72 pg/ml, P = 0.048). Increased amounts of IL-4 were also produced after stimulation with PHA (vaccinees 140 +/- 25; controls 40 +/- 40 ng/ml, P = 0.013) while levels of IFN-gamma and soluble IL-2 receptor were similar to controls and levels of IL-1 alpha (vaccinees 443 +/- 67; controls 792 +/- 118 pg/ml, P = 0.026) remained low. Addition of rIL-2 had little effect on these cytokine levels. These data suggest that Th2 cells producing IL-4 are preferentially activated by measures vaccine and may contribute to the immunologic abnormalities associated with immunization for measles and possibly other viral infections.
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PMID:Changes in cytokine production after measles virus vaccination: predominant production of IL-4 suggests induction of a Th2 response. 851 92

Human recombinant interleukin-10 (IL-10) was previously shown to inhibit accessory cell (AC)-dependent proliferation of bovine parasite-specific T helper 1 (Th1), Th2, and Th0 cells in an IL-2-reversible manner (Brown, W.C., Woods, V.M., Chitko-McKown, C.G., Hash, S.M., and Rice-Ficht, A.C., 1994. Infect. Immun. 62, 4697-4708). The present study was therefore designed to determine whether the effect of IL-10 on T cell proliferation corresponded with downregulated expression of cytokines, or their receptors, important for T cell growth. The effects of IL-10 on cellular proliferation and expression of IL-2, IL-4, IL-2 receptor (IL-2R; p55), and IFN-gamma by Babesia bovis- or Fasciola hepatica-specific Th cell clones were simultaneously evaluated. As shown previously, IL-10 strongly inhibited proliferation of all types of Th cell clones, although this did not correspond with reduced expression of IL-2 or IL-4 mRNA or their products. In contrast, expression of IL-2R mRNA was consistently reduced in the IL-10-treated clones. These results indicate that IL-10 does not inhibit AC-dependent proliferation of bovine Th cells by downregulating T cell cytokines; rather, IL-10 may act by downregulating IL-2R p55 expression and subsequent signal transduction leading to decreased cellular proliferation. IFN-gamma production was also consistently downregulated in the presence of IL-10.
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PMID:Interleukin-10 downregulates proliferation and expression of interleukin-2 receptor p55 chain and interferon-gamma, but not interleukin-2 or interleukin-4, by parasite-specific helper T cell clones obtained from cattle chronically infected with Babesia bovis or Fasciola hepatica. 856 14

In this study, we have investigated cytokine (IL-1 beta, IL-2, IL-5, IL-6, IFN-gamma, TNF-alpha) and T cell surface molecule (IL-2 receptor, CD28, CTLA-4) gene expression in two way mixed lymphocyte cultures (MLC) enhanced by concanavalin A (ConA) to assess whether this is a useful predictive method for severe graft-versus-host disease (GVHD) and graft failure in allogeneic bone marrow transplantation (allo BMT) patients. Our present study revealed increased mRNA expression of IL-2, IL-5 and IFN-gamma using this assay in patients with delayed engraftment followed by graft failure and patients who developed grade III acute GVHD. Elevated IL-2 and IFN-gamma levels in MLC medium were also observed in these patients. Concerning T cell surface molecule gene expression in our modified MLC, IL-2 receptor gene expression was not altered so much in allo BMT patients, however, CD28 and CTLA-4 gene expression were elevated in patients with graft failure and severe acute GVHD. The elevated expression of cytokines (IL-2, IL-5 and IFN-gamma) and T cell surface molecules (CD28 and CTLA-4) mRNA in our modified MLC, in patients who developed severe lethal transplantation-related complications may suggest an important role for these molecules in inducing a strong alloresponse. Therefore, the detection of increased gene expression of those molecules, in our modified MLC system, appeared to be useful for predicting transplantation-related complications in allo BMT patients. In addition, this modified MLC assay may also be useful for the selection of the most compatible related and unrelated donors.
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PMID:Transplantation-related complications predicted by cytokine gene expression in the mixed lymphocyte culture in allogeneic bone marrow transplants. 857 69

Mouse MHC class I-specific mAbs recognizing the alpha 1/alpha 2, but not those directed against the alpha 3 domain of the molecule, inhibited RNA, protein, and DNA synthesis of splenic T cells in response to stimulation through the TCR/CD3 complex. Similar inhibition was seen with LFA-1-specific mAbs under the same stimulation conditions. The effect of class I- and LFA-1-specific mAbs reflected a decrease of both IL-2 and IFN-gamma synthesis and IL-2 receptor alpha chain induction. IL-2, IL-2 receptor alpha chain, IFN-gamma, c-fos, c-jun, and c-myc mRNAs were not detected. Activation of AP-1 (c-Fos and c-Jun proteins) and NF-kappa B transcription factors were also inhibited. Inhibition was observed both after treatment of cells in culture and after intravenous injection of Abs in mice. Although bulk phosphorylation was inhibited, early tyrosine phosphorylation and calcium ion influx were normally induced. Protein phosphatase inhibitors did not reverse this inhibition, ruling out an enhanced activation of these enzymes in the observed inhibition. Cell surface expression of one of early PKC activation marker, CD69 was also inhibited. Phorbol esters that directly activate PKC prevented inhibition. Thus, class I molecules are implicated in signal transduction involved at an early stage for T cell activation in a manner that suggests their implication in accessory signal transmission that contributes to the regulation of PKC activity.
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PMID:MHC class I molecules are implicated in costimulatory signals during TCR/CD3-induced activation. 859 31

The marked tropism of human herpesvirus-6 (HHV-6) for natural killer (NK) cells and T lymphocytes has led us to investigate the effect of HHV-6 on cellular cytotoxicity. We describe here how HHV-6 infection of peripheral blood mononuclear cells (PBMC) leads to upregulation of their NK cell cytotoxicity. The induction of NK cell activity by HHV-6 was abrogated by monoclonal antibodies (mAbs) to IL-15 but not by mAbs to other cytokines (IFN-alpha, IFN-gamma, TNF-alpha, TNF-beta, IL-2, IL-12) suggesting that IL-15 secreted in response to viral infection was responsible for the observed effect. Furthermore, NK activation by HHV-6 was blocked with mAb to CD122, as well as by human anti-HHV-6 neutralizing antibodies. Using RT-PCR, we were able to detect IL-15 mRNA upregulation in purified monocyte and NK cell preparations. IL-15 protein synthesis was increased in response to HHV-6. Finally, addition of IL-15 to PBMC cultures was found to severely curtail HHV-6 expression. Taken together, our data suggest that enhanced NK activity in response to viral infection represent a natural anti-viral defense mechanism aimed at rapidly eliminating virus-infected cells.
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PMID:Human herpesvirus-6 enhances natural killer cell cytotoxicity via IL-15. 861 68

We previously reported the generation and characterization of a panel of CD4(+) autoreactive T cell clones that suppress development of autoimmune diabetes in non-obese diabetic (NOD) mice. We showed that the protective capacity of the T cell clones correlated with secretion of an activity that potently inhibits allogeneic mixed lymphocyte reaction (allo-MLR). In this report, we describe the biological characteristics of the allo-MLR inhibitory activity (MLR-IA, short for mixed lymphocyte reaction inhibitory activity) secreted by the protective T cell clone, NOD-5. MLR-IA has little effect on initiation of proliferation in an allo-MLR, but it potently inhibits the maintenance and amplification of the proliferative response. MLR-IA is also capable of inhibiting concanavalin A (Con A) stimulated splenic responder T cell proliferation. MLR-IA is reversible in vitro and is not restricted by MHC class I or II proteins. MLR-IA does not affect IL-2 receptor expression of responding T cells and has no effect on IL-2-dependent proliferation of CTLL-20 T cells. Partially purified MLR-IA inhibits IL-2 production in a primary allo-MLR, and decreases IFN-gamma production during secondary allo-MLR and Con A activation, whereas it enhances IL-4 production in both primary and secondary Con A activation. MLR-IA is not neutralized by combination of antibodies specific for transforming growth factor-beta, IL-10, tumor necrosis factor-alpha/beta or IFN-gamma, suggestive of a novel activity. MLR-IA is ammonium sulfate precipitable, sensitive to protease digestion and is destroyed by boiling, indicating that a protein moiety is part of its active structure. Our work suggests that a potentially novel immunoregulatory activity, capable of inhibiting T lymphocyte proliferation and IFN-gamma production, and stimulating IL-4 production, may regulate development of autoimmune diabetes in NOD mice.
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PMID:Biological characteristics of an immunoregulatory activity secreted by an autoreactive CD4+ T cell clone that suppresses autoimmune diabetes in non-obese diabetic mice. 867 56

Experimental infections of mice with the African trypanosome Trypanosoma brucei lead to a profound state of T-cell unresponsiveness in the lymph node cell (LNC) compartment. This suppression is mediated by macrophage-like cells which inhibit interleukin 2 (IL-2) secretion and down-regulate IL-2 receptor expression (M. Sileghem, A. Darji, R. Hamers, M. Van de Winkel, and P. De Baetselier, Eur. J. Immunol. 19:829-835, 1989). Similar suppressive cells can be generated in vitro by pulsing 2C11-12 macrophage hybridoma cells with opsonized T. brucei parasites (2C11-12P cells). Cocultures of 2C11-12P cells and LNCs secrete higher levels of gamma interferon (IFN-gamma), and the hyperproduction of IFN-gamma was found to be confined to CD8+ lymphoid cells. Elimination of CD8+ cells from cocultures of 2C11-12P cells and LNCs restores the T-cell proliferative response. Furthermore, addition of neutralizing anti-IFN-gamma antibodies to the cocultures reduces the level of suppression and concomitantly restores the level of IL-2 receptor expression. Hence, IFN-gamma plays a cardinal role in this in vitro model for T. brucei-elicited immunosuppression. Cocultures of LNCs and 2C11-12P cells in a two-chamber culture system further demonstrated that cell-cell contact is required for hyperproduction of IFN-gamma and, moreover, that IFN-gamma cooperates with a 2C11-12P-derived diffusible factor to exert its suppressive activity. Finally, tumor necrosis factor alpha (TNF-alpha produced by 2C11-12P cells was found to be implicated in the hyperproduction of IFN-gamma, since addition of neutralizing anti-TNF-alpha antibodies to cocultures reduced the level of suppression and concomitantly abrogated the hyperproduction of IFN-gamma. Collectively, our findings indicate that T. brucei-elicited suppressive 2C11-12 macrophage cells differentially influence T-cell subpopulations: (i) CD8+ cells are signaled via cell-cell contact to produce IFN-gamma, and TNF-alpha is implicated in this process, and (ii) locally produced IFN-gamma and macrophage-released factors act in concert to inhibit CD4+ and CD8+ T-cell proliferative responses.
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PMID:In vitro simulation of immunosuppression caused by Trypanosoma brucei: active involvement of gamma interferon and tumor necrosis factor in the pathway of suppression. 867 90

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


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