Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: DrugBank:BIOD00082 (IL-2)
 29,198 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biological effects of human natural tumor necrosis factor-alpha (TNF) on glioblastoma cells in vitro and on glioma patients were investigated. TNF treatment on glioblastoma cells, even at a high dose (256 U/ml), exhibited no remarkable cytocidal activity in MTT assay, but at lower doses significantly inhibited colony forming and DNA synthesis. TNF at a low dose (10 U/ml) stimulated production of prostaglandin E2, Mn-superoxide dismutase, interleukin (IL)-6 and IL-8 by glioblastoma cells. These results indicated that the direct effect of TNF on human glioblastoma cells is rather antiproliferative than cytotoxic and is to modulate their metabolic pathways. In an early Phase I clinical trial, TNF was administered intracranially to six patients bearing glioblastoma. In this trial, the author studied in vivo immunological responses in the cerebrospinal fluid and regional fluid after the regional TNF injections. TNF in these body fluids were detected with a half life of several hours. There occurred a substantial number of leukocyte migration after the TNF administration. Neutrophils appeared first peaking at 8 to 12 hours, and then CD4+CD8-T cells and CD11b+CD13+CD14+ monocytes followed. IL-8 activity in the cerebrospinal fluid simultaneously corresponded to peak of the neutrophil migration. Increases in IL-6, IL-1 beta and prostaglandin E2 levels in the cerebrospinal fluid, regional fluid or both occurred peaking at 8 to 12 hours after TNA infection. Neither IL-2 nor interferons was detected. In conclusion, TNF may act as an antineoplastic agent by its direct cytostatic effects and indirectly through immune modulatory effects.
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PMID:[In vitro and in vivo immunobiological responses of glioblastoma to human natural tumor necrosis factor-alpha]. 142 94

The influence of cytokines on extracellular superoxide dismutase (EC-SOD) expression by human dermal fibroblasts was investigated. The expression was markedly stimulated by interferon-gamma (IFN-gamma), was varying between fibroblast lines stimulated or depressed by interleukin-1 alpha (IL-1 alpha), was intermediately depressed by tumor necrosis factor-alpha (TNF-alpha), and markedly depressed by transforming growth factor-beta (TGF-beta). TNF-alpha, however, enhanced the stimulation by a high dose of IFN-gamma, whereas TGF-beta markedly depressed the stimulations given by IFN-gamma and IL-1 alpha. The ratio between the maximal stimulation and depression observed was around 30-fold. The responses were generally slow and developed over periods of several days. There were no effects of IFN-alpha, IL-2, IL-3, IL-4, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor, human growth hormone, Escherichia coli lipopolysaccharide, leukotriene B4, prostaglandin E2, formylmethionylleucylphenylalanine, platelet-activating factor, and indomethacin. The cytokines influencing the EC-SOD expression are also known to influence superoxide production by leukocytes and other cell types, and the EC-SOD response pattern is roughly compatible with the notion that its function is to protect cells against extracellular superoxide radicals. The results show that EC-SOD is a participant in the complex inflammatory response orchestrated by cytokines. The CuZn-SOD activity of the fibroblasts was not influenced by any of the cytokines, whereas the Mn-SOD activity was depressed by TGF-beta. TNF-alpha, IL-1 alpha, and IFN-gamma stimulated the Mn-SOD activity, as previously known, and these responses were reduced by TGF-beta. The different responses of the three SOD isoenzymes illustrate their different physiological roles.
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PMID:Regulation by cytokines of extracellular superoxide dismutase and other superoxide dismutase isoenzymes in fibroblasts. 155 78

Peripheral blood polymorphonuclear neutrophils (PMN) can significantly inhibit lymphokine-activated killer- (LAK) mediated cytotoxicity when added to a cytotoxicity assay of IL-2-activated PBL and target cells. The inhibition by resting PMN is resistant to blocking with catalase and superoxide dismutase, suggesting that reactive oxygen species are not involved. The addition of TNF greatly enhanced the PMN-mediated inhibition of LAK effector functions. This TNF-enhanced inhibition is reversed by catalase, but not by superoxide dismutase, implicating hydrogen peroxide in the augmented inhibition. Separation of PMN from effector cells and target cells totally abrogates the inhibition by both resting PMN and TNF-treated PMN. Formalin-fixed PMN, heat-treated PMN, PMN lysates, and PMN membrane all fail to mediate any inhibition of LAK. These results suggest that contact with intact viable PMN is needed for inducing LAK inhibition. However, pretreatment of LAK cells with PMN also decreases their cytotoxicity in subsequent chromium release assays. PMN can also inhibit NK cytotoxicity of fresh PBL. However, NK activity is much less sensitive to inhibition by resting PMN than is LAK. TNF also augments PMN inhibition of NK, and there is no significant difference between LAK and NK in sensitivity to the TNF-enhanced inhibition. Our results indicate that PMN can significantly influence the destruction of tumor targets by LAK and NK, and suggest that approaches to circumvent such regulation may be important in the outcome of immunotherapies with IL-2 and LAK cells.
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PMID:Inhibition of lymphokine-activated killer- and natural killer-mediated cytotoxicities by neutrophils. 278 46

Peripheral blood polymorphonuclear neutrophils (PMN) suppressed the induction of PBL lymphokine-activated killer (LAK) function by rIL-2 in vitro. The suppression depended on the concentration of PMN in the IL-2 culture, and required intact PMN. However, PMN did not require treatment with immunoregulators such as IL-2, LPS, or TNF to express the suppressive activity, and no direct contact with PBL was needed for the suppression. Addition of anti-TNF antibodies had no effect on the suppression, suggesting that no endogenous TNF in the culture was involved in the suppression. PMN did not inhibit LAK function by preventing utilization of IL-2 by PBL or by selective depletion of NKH-1+ cells which constitute the majority of LAK precursors in PBL. The suppression was reversed by superoxide dismutase but not by catalase, suggesting that superoxide anion, not hydrogen peroxide, was involved in the suppression. No other suppressive factor was detectable in PMN culture supernates. Our results of PMN regulating LAK induction in vitro suggest that PMN may have a role in determining the outcome of immunotherapy with IL-2 in vivo.
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PMID:Suppression of lymphokine-activated killer induction by neutrophils. 326 11

Food restriction delays the loss of several cellular immune functions, retards the onset of many diseases during aging and, consequently, extends life span significantly in laboratory rodents. The present study was undertaken to determine whether the age-associated loss in immune function is linked to changes in microsomal and mitochondrial membranes of spleens in Fischer-344 (F-344) male rats. In this study, we determined cytosolic superoxide dismutase activity (SOD), fluidity and cholesterol content in the splenic microsomal and mitochondrial membranes, and DNA synthesis and IL-2 production in spleen cells from young and old ad libitum-fed (AL) and food restricted (FR) rats. The results show that proliferative response to phytohemagglutinin (PHA) and concanavalin A (Con-A) was significantly higher in the spleen cells of 18-month- and 24-month-old FR rats, as compared to their age-matched AL controls. Cytosolic SOD activity in the 24-month-old AL rats decreased by 28% as compared to 6-month-old AL rats, whereas in FR old rats, the loss was only 12%, suggesting that food restriction prevents loss in cytosolic SOD activity in spleens. Our data are consistent with the notion that food restriction modulates loss in immune response of splenocytes by maintaining both cytosolic SOD activity and membrane fluidity during aging.
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PMID:Modulation of antioxidant activities and immune response by food restriction in aging Fisher-344 rats. 759 47

Infection with a sexually transmitted disease (STD) increases the risk for human immunodeficiency virus (HIV) infection. Polymorphonuclear leukocytes (PMNs) are recruited into the genital tract by STD pathogens, such as Chlamydia trachomatis. Semen of HIV-infected men contains HIV associated with mononuclear cells. This study investigated the interaction among PMNs from HIV-uninfected persons, C. trachomatis, and HIV-infected cells and examined the mechanisms for enhanced HIV replication. We demonstrated that PMNs from HIV-seronegative donors induced HIV replication in mononuclear cells from 17 HIV-infected patients in medium without exogenous IL-2. HIV in the cell-free supernatants from cocultures of PMNs and patients' peripheral blood mononuclear cells (PBMCs) was replication competent, as indicated by their capacity to propagate HIV in a second round of culture using PBMCs from HIV-seronegative individuals and by the fact that proviral DNA was found in these cells. PMNs from HIV-seronegative donors increased HIV replication over 100-fold in chronically HIV-infected cell lines of the monocytic, T, and B cell lineages. Moreover, PMNs increased U1 cells' production of p24 antigen by as much as ninefold when compared with U1 cells cocultured with PBMCs. The addition of C. trachomatis to PMN and U1 coculture increased HIV replication by an additional ninefold at 24 h, whereas C. trachomatis alone had no effect on p24 antigen production by U1 cells. Thus, C. trachomatis serves not only to recruit PMNs, but also to interact with PMNs to increase HIV replication. HIV replication is triggered by contact of HIV-infected cells with PMNs, by the generation of reactive oxygen intermediates (ROIs), and by soluble factors such as TNF-alpha and IL-6. This is based on the findings that production of p24 antigen, IL-6, and TNF-alpha induced by PMNs is abrogated by disrupting or partitioning PMNs from HIV-infected cells; is inhibited by superoxide dismutase and catalase, enzymes that destroy ROIs; is enhanced by differentiated HL60 cells capable of producing ROIs; and is induced by PMNs tested negative for CMV. Furthermore, the production of ROIs is independent of HIV infection of mononuclear cells, since PMNs cocultured with HIV-uninfected parental monocytic and T cell lines generated ROIs. Therefore, the increased risk for acquiring HIV infection associated with chlamydia cervicitis may be related to the local recruitment of PMNs by C. trachomatis and the induction of infectious virus from mononuclear cells present in semen. These observations provide a rationale for strategies to reduce HIV transmission by control of STD.
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PMID:Neutrophils from human immunodeficiency virus (HIV)-seronegative donors induce HIV replication from HIV-infected patients' mononuclear cells and cell lines: an in vitro model of HIV transmission facilitated by Chlamydia trachomatis. 769 32

Blood lymphocytes of cancer patients lysed autologous, freshly isolated tumor cells. The autologous tumor-killing (ATK) activity is strongly associated with postoperative clinical course, indicating that ATK is a meaningful prognostic indicator and provides evidence for immunological control of tumor growth and metastasis. Large granular lymphocytes (LGL) with ATK activity released a soluble cytotoxic factor(s), termed LGL-CF (LGL-derived cytotoxic factor) during interaction with autologous tumor cells. The cytotoxic factor lysed autologous and allogeneic freshly isolated human tumor cells, while they were resistant to any of recombinant cytokines, including tumor necrosis factor (TNF), lymphotoxin (LT), interferon (IFN) alpha, IFN gamma, interleukin (IL)-1 alpha and IL-2. Biological activity of LGL-CF was not abrogated by monoclonal and polyclonal antibodies against these cytokines. LGL-CF also exhibited lysis of a variety of tumor cell lines, but not of nonmalignant cells. Actinomycin D augmented the lysis of LGL-CF. LGL-CF was stable at 56 degrees C, but was destroyed at 100 degrees C. Treatment of LGL-CF with trypsin or proteinase K reduced or abrogated the lytic effect, respectively, while it was resistant to papain, catalase, and superoxide dismutase. These results indicate that LGL produce a novel cytotoxic factor in response to autologous tumor cells that mediates lysis of fresh human tumor cells.
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PMID:Role of NK cell cytotoxic factor against fresh human tumors. 825 31

Recent investigations demonstrate that B lymphocytes possess an oxygen-generating system which is similar to the phagocytic NADPH-oxidase system. Reduction of nitroblue tetrazolium by stimulated tonsillar B cells is inhibited by superoxide dismutase (SOD). However, the biological significance of the superoxide-generating property of B cells remains to be explored. In this study, we examined the immunomodulatory effect of a recombinant human SOD (rh-SOD) on the activation of human B lymphocytes in vitro. A supplement of rh-SOD in the B cell culture increased the proliferation of unstimulated B cells in the presence of SAC, but not of SAC-preactivated B cells in the presence of cytokines such as IL-2 or IL-4. In addition, rh-SOD enhanced the immunoglobulin generation by B cells at the terminal stage of differentiation. Inactivation of the enzymatic activity of SOD by treatment with anti-SOD antibody abrogated the enhancing effects. These data suggest that the superoxide-generating system in B cells may be involved in the cellular activation process.
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PMID:Immunomodulatory effect of recombinant human superoxide dismutase (SOD) on human B lymphocyte function in vitro. 880 8

Eicosapentaenoic acid and docosahexaenoic acid (EPA and DHA respectively) can suppress the production of interleukin-1 (IL-1), IL-2 and TNF (tumor necrosis factor) but not of IL-4 by human lymphocytes in vitro. In addition, the concentrations of EPA and DHA were also found to be low in the plasma phospholipid fraction of patients with SLE. In a limited clinical study performed by us earlier, it was observed that oral supplementation of EPA/DHA to patients with SLE can induce clinical remission without any side-effects. Since oxygen free radicals are known to be involved in the pathobiology of SLE, we estimated the plasma concentrations of lipid peroxides, nitric oxide, and anti-oxidants such as catalase, superoxide dismutase (SOD), glutathione peroxidase and vitamin E in these patients both before and after the induction of remission following EPA/DHA administration. These results showed that the levels of lipid peroxides are elevated and those of nitric oxide, SOD and glutathione peroxidase are decreased in SLE prior to EPA/DHA supplementation. Following EPA/DHA administration the concentrations of lipid peroxides, and those of nitric oxide, SOD and glutathione peroxidase reverted to near normal levels. These results suggest that oxidant stress, nitric oxide, and anti-oxidants play a significant role in SLE and that EPA/DHA can modulate oxidant stress and nitric oxide synthesis and may have a regulator role in the synthesis of anti-oxidant enzymes such as SOD and glutathione peroxidase. From the results of this study, we would like to suggest that measurement of lipid peroxides, nitric oxide and anti-oxidants can be used as markers to predict prognosis in patients with SLE.
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PMID:Oxidant stress, anti-oxidants and essential fatty acids in systemic lupus erythematosus. 908 97

We examined the effects of various neurotrophic factors and cytokines on 6-hydroxydopamine (6-OHDA)-induced toxicity in PC12 cells. Exposure of PC12 cells to 6-OHDA resulted in a concentration- and time-dependent cell death, as evidenced by the release of lactate dehydrogenase into the culture medium. Addition of catalase, but not superoxide dismutase, to the culture medium protected PC12 cells from the 6-OHDA-induced toxicity. Interleukin (IL)-6 provided a dose-dependent protection against the 6-OHDA toxicity, as did nerve growth factor (NGF). In addition, basic fibroblast growth factor and dibutyryl cyclic AMP partially protected PC12 cells from 6-OHDA toxicity. Neither IL-1alpha, IL-2, IL-4, transforming growth factor-beta, nor leukemia inhibitory factor had any effect. The protective effect of IL-6 was attenuated by 3-amino-1,2,4-triazole, an inhibitor of catalase. These results suggest that IL-6 may protect PC12 cells against the 6-OHDA toxicity by activating free radical detoxifying mechanisms, such as catalase activity.
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PMID:Possible involvement of catalase in the protective effect of interleukin-6 against 6-hydroxydopamine toxicity in PC12 cells. 925 29


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