DrugBank:BIOD00082 - FACTA Search

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Query: DrugBank:BIOD00082 (IL-2)
29,198 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine kinases of the src family, p56lck and p59fyn, were implicated in the transduction of signals via the T-cell receptor complex. These kinases are negatively regulated by phosphorylation of a carboxyl-terminal tyrosine residue. Tyrphostins are synthetic low molecular weight compounds that selectively inhibit different protein tyrosine kinases. We report here on the agonistic and antagonistic effects of tyrphostins on human peripheral blood mononuclear cells (PBM). At low concentration, the tyrphostins enhanced glucose uptake and maximal stimulation was attained at a concentration characteristic for each of the tyrphostins used. Higher concentrations were less effective. The tyrphostins AG126 and AG183 were also found to enhance IL-2-induced cytotoxicity in human PBM in a biphasic manner. In contrast, the tyrphostin AG17 markedly inhibited IL-2-induced cytotoxicity at low AG17 concentration and no stimulation was observed. The tyrphostins tested had selective effects on [3H]thymidine incorporation induced by the mixed lymphocyte culture and different agents. The most potent inhibitor was AG17. Tyrphostins also affect cytokine secretion by human PBM. AG126 and AG183 enhanced TNF-alpha secretion and this effect was more prominent in the presence of IL-2. AG126 enhanced IFN-gamma, IL-1, and IL-6 production in PBM that were costimulated with the stress stimuli heat shock and phenylarsine oxide. The stimulatory effects of the tyrphostins on cytokine secretion and induction of cytotoxicity might be interrelated. The agonistic and antagonistic effects of tyrphostins on lymphocyte functions may have therapeutic potential.
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PMID:Agonistic effects of tyrphostins on human peripheral mononuclear cells. 139 36

The cytochalasans, fungal metabolites that interact with actin, can affect lymphocyte proliferation; high concentrations inhibit lectin-induced proliferation and low concentrations augment it. The phorbol ester tumor promoter, PMA, alone is not mitogenic for primary lymphocytes but enhances the activity of mitogenic lectins. Because the cytochalasans have been reported to increase intracellular Ca2+ and because PMA activates protein kinase C, lymphocytes were treated with PMA and cytochalasin B (CyB) to determine if this combination would induce DNA synthesis. While this treatment by itself did not cause proliferation, lymphocytes cultured with PMA and CyB overnight, washed, and recultured with IL-2 proliferated to the same degree as lymphocytes stimulated with Con A. Three different cytochalasans, cytochalasin B, cytochalasin D, and chaetoglobosin C, all of which bind to cellular actin with different affinities and only one of which affects glucose transport, induced IL-2 receptors in combination with PMA. Flow cytometric analysis with an antibody to the IL-2 receptor alpha subunit confirmed the induction of receptors on CD8+ cells. However, no IL-2 was produced after the exposure of lymphocytes to the combination of cytochalasans and PMA. Therefore, there was sufficient signal to induce IL-2 receptor expression but not to induce IL-2.
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PMID:Cytochalasans and PMA induce IL-2 receptors on CD8+ lymphocytes. 139 84

We have previously reported that IL-2-induced lymphokine-activated killer (LAK) cells have the capacity to lyse autologous and allogeneic monocytes. To understand the biologic significance of this interaction, we investigated the function of human monocytes against the opportunistic pathogen, Candida albicans, subsequent to a short exposure to autologous LAK cells. A highly sensitive radiolabel assay, which makes use of the incorporation of [3H]glucose into residual Candida after their incubation with monocytes, was developed to measure antifungal activity. Cultured monocytes, after 2 to 6 h exposure to LAK cells, were found to be substantially suppressed in their ability to control fungal growth. Moreover, monocytes cultured in the presence of granulocyte/macrophage (GM)-CSF or IL-3, were even more suppressed in function after a short incubation with LAK cells. The effect of GM-CSF was both time and dose dependent, with peak susceptibility induced after 4 days of culture with as little as 10 U/ml of the cytokine. These GM-CSF-cultured monocytes, however, were relatively resistant to inhibition by freshly isolated large granular lymphocytic NK cells. Therefore, IL-2 induces in large granular lymphocytic cells the capacity to inhibit monocyte function. In contrast to GM-CSF and IL-3, IFN-gamma was found to have a protective effect on monocytes, because monocytes cultured 4 days in IFN-gamma were not significantly inhibited by LAK cells. These results indicate that LAK cells may be involved in regulation of monocyte function and suggest that the state of differentiation induced by different cytokines may dictate the level of control of the monocytes by LAK cells.
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PMID:Suppression of human monocyte function against Candida albicans by autologous IL-2-induced lymphokine-activated killer cells. 189 5

Hemopoietic cells have an absolute requirement for survival and proliferation for specific growth factors. The growth factors maintain the critical vitality of the cells by stimulating adenosine triphosphate (ATP) synthesis and hexose transport. Intracellular alkalinization also occurs rapidly through the stimulation of the Na+/H+ antiporter. These immediate metabolic events, not initiated by serum components, appear to be necessary for the integrity of cellular viability (Fig. 6). Interleukin-3 has been shown to induce the activation of PK-C through a mechanism(s) not requiring the hydrolysis of phosphoinositol 4,5 bisphosphate. A role for Ca2+ influx or intracellular release in the action of CSFs or interleukins has not been shown. Although downregulation of cAMP has been reported in response to IL-2, the signal transduction process of CSFs and IL-2 appears not to be mediated by upregulation of cyclic nucleotide metabolism or "classical" phospholipid degradative pathways. Protein phosphorylation is clearly modulated by the hemopoietic cytokines, yet only the CSF-1 receptor has any known intrinsic kinase activity. Instead, the IL-3, GM-CSF receptors, and perhaps G-CSF appear to be coupling to kinases of both tyrosine and serine specificities. This may be a direct allosteric interaction with membrane-associated kinases or transduced through an intermediate protein such as those using GTP. Such is the case for many hormone receptors that couple to amplifying "second messenger" enzyme systems (i.e., adenylate cyclase, phospholipase C) or members of the insulin growth factor family that couple to tyrosine kinases in proximity to the receptors (IGF-II). One of the kinase systems that IL-2, IL-3, and other CSFs stimulate appears to have some characteristics similar to PK-C. Direct activators of PK-C stimulate some similar serine-threonine phosphorylation and perhaps even tyrosine phosphorylation. The hemopoietic growth factors, however, stimulate tyrosine phosphorylation of some proteins that are not phosphorylated in response to PK-C activators, suggesting that these kinase systems are independently regulated. Although phorbol esters stimulate many of the same metabolic activities (ATP synthesis in myeloid and lymphoid cell lines), growth-factor abrogation is clearly associated with the action of tyrosine kinase oncogenes or the nuclear oncogene effectors such as v-myc. It is likely, therefore, that tyrosine kinases are playing a critical role in the control of proliferation although the dominant amount of cellular protein phosphorylations are on serine. Both classes of kinases are apparently required for growth-factor action. All the hemopoietic growth factors examined thus far stimulate the steady-state accumulation of the nuclear protooncogenes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hematopoietic growth-factor signal transduction and regulation of gene expression. 209 Feb 58

Lactate is a product of glycolytically active macrophages. After stimulation with concanavalin A accessory cell-depleted splenic T-cell populations were found to produce only minute amounts of T-cell growth factor (TCGF); but substantial amounts of TCGF were produced if the cultures were supplemented either with splenic adherent cells or with lactate but not with interleukin-1 (IL-1). IL-1 was capable, however, of supporting TCGF production by the thymoma subline EL4-6.1. TCGF production in cultures of accessory cell-depleted splenic T-cell populations was demonstrable with 10(-3) M L-lactate, and optimal responses (plateau level) were obtained with 4-6 X 10(-2) M L-lactate. Cultures of macrophages were found to accumulate up to 5 X 10(-2) M lactate. Our experiments indicate, therefore, that lactate serves as a regulatory signal by which macrophage-like accessory cells enhance helper-T-cell functions. Lactate is apparently not the only mediator of accessory cell function since plateau levels of TCGF production were markedly lower with lactate than with splenic accessory cells; but L-lactate was found also to determine the magnitude of T-cell-mediated immune responses in vivo and in cultures of unfractionated lymphocyte populations. The production of interferon in accessory cell-depleted and concanavalin A-treated T-cell cultures, however, was not significantly affected by lactate. Concanavalin A-stimulated splenic T-cell populations were found to consume glucose rapidly and to release lactate into the supernatant. This indicates that the cells contain more lactate and pyruvate than they can utilize by their respiratory metabolism. The administration of external lactate or pyruvate was found to inhibit the utilization of glucose by the mitogenically stimulated T cells.
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PMID:Regulation of T-cell functions by L-lactate. 349 29

An inhibitor of lectin-induced splenocyte proliferation from serum of normal chickens has been characterized. This suppressive factor, found in both serum and plasma and at concentrations as low as 3%, causes a 50% inhibition in proliferative responses to T-cell lectins of autologous and heterologous lymphoid cells. The inhibitor in serum also dramatically suppresses murine IL-2 synthesis, proliferation of murine spleen cells stimulated with PHA, and synthesis of DNA in xenogeneic-transformed mammalian lymphoblastoid cell lines. Serum does not block binding of the lectin to lymphoid cells and the suppressive activity cannot be overcome by any dose of lectin. The inhibitor of DNA synthesis is destroyed by pepsin. NH4(2)SO4 (50%) and TCA (15%) treatments both precipitate the suppressor factor, which further indicates that the suppressive factor is a protein. A 330-fold purification of the inhibitory protein from serum was obtained when boiled serum was passed over a Sepharose 6B and then a DEAE-Sephacel column which was washed at pH 5.0 and eluted with 0.2 M NaCl. SDS-PAGE with silver staining revealed a nonreduced protein with an apparent molecular weight of 61 kDa. Less than 2 micrograms of the protein thus obtained caused a 50% inhibition in the proliferation of chicken lymphoid cells to Con A. The inhibitor of DNA synthesis is therefore not cytotoxic, does not bind to Con A or to mannose or glucose residues on lymphocytes, is acid and heat stable, and is associated with a protein that has a molecular weight of 61 kDa. Since such low concentrations of this naturally occurring, proteinaceous, immunosuppressive factor cause substantial inhibition of IL-2 synthesis and proliferative activity of T cells, this protein may be a very important immunomodulator.
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PMID:A soluble 61-kDa protein is associated with inhibition of lectin-induced proliferation and IL-2 synthesis. 349 67

Virus induced IFN (IFN alpha or beta) suppresses the antibody response in both mouse and human. The suppression may be related to IFN effect on intermediary metabolism (inhibition of hexose monophosphate shunt) which could result in activation of protein kinase activities. Immune IFN (IFN gamma) also suppresses the antibody response with purified IFN gamma more effective than crude, suggesting that crude IFN gamma preparations contain an antagonist. The cellular interactions that regulate IFN gamma production are similar to those for antibody production with helper and suppressor cell activities. T-cell growth factor or interleukin 2 will mediate helper cell requirements and appears to be an absolute requirement for IFN gamma production.
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PMID:Effect of interferon on antibody formation. 618 7

Oral administration of autoantigens suppresses development of autoimmunity in several animal models, and is being tested in clinical trials in patients with autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Non-obese diabetic (NOD) mice spontaneously develop insulin-dependent diabetes mellitus at 15 to 20 weeks of age, after mononuclear cell (MNC) infiltration of the pancreatic islets of Langerhans and destruction of insulin-producing beta cells. We have previously shown that oral administration of insulin suppresses insulitis and development of diabetes in the NOD mouse. Oral insulin has no metabolic effect on blood glucose. Oral insulin mediates its effect through a T cell-dependent mechanism as shown by adoptive transfer and T cell depletion experiments, but the mechanisms responsible have not been fully explored. We now report a serial analysis of the cells and cytokines associated with development of diabetes in NOD mice, and contrast this with the findings in animals fed equine insulin or a control protein (ovalbumin). Animals were fed 1 mg twice a week for 5 weeks, beginning at 5 weeks of age. Marked insulitis in naive or ovalbumin-fed NOD mice occurred at 10 weeks, at which time a dense peri-islet and intra-islet MNC infiltration was observed. Immunohistological studies using monoclonal antibodies showed that infiltrating MNC consisted mainly of CD4+ T cells ( > 75% of leukocytes) plus smaller numbers of macrophages and CD8+ T cells. These cells displayed evidence of immune activation with expression of receptors for interleukin-2 (IL-2R) plus Th1 cytokines; dense labeling for IFN-gamma and tumor necrosis factor-alpha, plus lesser amounts of IL-2, was observed. MNC lacked labeling for IL-4, IL-10, prostaglandin-E, or transforming growth factor-beta. By contrast, at 10 weeks, pancreatic tissues from NOD mice fed insulin showed considerably less insulitis, and the residual MNC, although still largely CD4+ T cells plus macrophages, showed dense labeling for IL-4, IL-10, prostaglandin-E, and transforming growth factor-beta and an absence of IL-2, IFN-gamma or tumor necrosis factor-alpha Taken together with our previous findings, these data indicate that oral administration of insulin affects the development of diabetes in NOD mice through the generation of cells that elaborate immunoregulatory cytokines within the target organ and shift the balance from a Th1 to a Th2 pattern of cytokine expression.
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PMID:Suppression of insulitis in non-obese diabetic (NOD) mice by oral insulin administration is associated with selective expression of interleukin-4 and -10, transforming growth factor-beta, and prostaglandin-E. 748 82

Peripheral blood mononuclear cells from patients with non-insulin-dependent diabetes mellitus (NIDDM) show reduced proliferative response to phytohemagglutinin (PHA) and other mitogens. This study was undertaken to determine whether this reduced lymphocyte proliferation is mediated by a decreased production of cytokine or decreased expression of interleukin-2 receptor (IL-2R). Mononuclear cells from NIDDM patients (n = 34) and healthy controls (n = 22) were cultured in RPMI-1640 media containing PHA, concanavalin-A and phorbol myristate acetate. NIDDM patients showed reduced [3H]thymidine uptake (57% of controls, P < 0.01), reduced percentage of IL-2R-positive cells (61% of controls, P < 0.02) and increased level of tumor necrosis factor (TNF)-alpha (200% of controls, P < 0.05). The percentage of complement receptor (CR) 3-positive monocytes from NIDDM patients was also decreased (72% of controls, P < 0.05). However, the production of IL-1 beta, IL-2 and interferon-gamma, the percentages of pan T cells (CD3), T helper cells (CD4), T suppressor cells (CD8), the ratio of CD4/CD8 and the expression of CR1 and Fc receptors for immunoglobulin G (Fc gamma RII and Fc gamma RIII) were not significantly different between NIDDM patients and healthy subjects. Human recombinant IL-2 was unable to restore the [3H]thymidine uptake by PHA-stimulated mononuclear cells from NIDDM patients. Elevation of glucose concentration up to 27.8 mmol/l in the culture medium did not suppress the [3H]thymidine uptake and IL-2R expression by activated lymphocytes from healthy subjects. The decreased expression of IL-2R on activated lymphocytes might be responsible for the insufficient lymphocyte proliferation in NIDDM patients. These findings suggest that decreased expression of CR3 on monocytes, decreased lymphocyte proliferation and decreased IL-2R expression despite a higher production of TNF-alpha may explain the impaired cell-mediated immunity seen in NIDDM patients.
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PMID:Decreased cell-mediated immunity in patients with non-insulin-dependent diabetes mellitus. 758 21

We have explored the mechanism of stimulation of glucose transport during PHA stimulation of human peripheral blood lymphocytes (HPBT) enriched in T cells. Equilibrium exchange flux of 3-O-methyl glucose (3-O-MG) was stimulated two- and fourfold at 24 and 48 h after PHA stimulation, respectively. The increase was transient in that the flux rate returned to control (unstimulated) levels by 96 h. Immunoblotting and immunoprecipitation using specific Abs revealed that resting HPBT expresses glucose transporter isoforms GLUT-2 and GLUT-3 but not GLUT-1. After PHA stimulation, GLUT-1 expression was induced predominantly in the plasma membrane, whereas GLUT-3 expression was simultaneously down-regulated. GLUT-1 expression was detectable at 24 h, peaked at 48 h, and disappeared at 96 h. The total number of glucose transporters per cell measured as the total capacity of D-glucose displaceable cytochalasin B binding did not change significantly at any time after PHA stimulation. PHA stimulation also caused expression of high affinity IL-2R and secretion of IL-2. The IL-2 secretion was transient, which peaked at 24 h, slightly preceding the GLUT-1 expression peak and disappeared at 72 h. In PHA-activated HPBT cells synchronized at G0-G1, GLUT-1 was not expressed but was rapidly induced by exposure to IL-2. This induction did not occur in the presence of cyclosporin A, which inhibits IL-2 secretion. Based on these observations, we conclude that PHA stimulation increases glucose transport partly by inducing the expression of GLUT-1 instead of GLUT-3 and that GLUT-1 expression is induced by signals generated by IL-2 binding to its high affinity receptors.
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PMID:Changes in glucose transport and transporter isoforms during the activation of human peripheral blood lymphocytes by phytohemagglutinin. 814 74

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