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

We have previously shown that transfection of a plasmid clone containing full length human IFN-gamma genomic DNA into a murine T-lymphoblastoid line is followed by basal expression of the transfected gene, with increased transcription occurring upon stimulation of the cells with either phorbol ester or IL-2. In addition, upon transfection of this DNA into murine fibroblasts, high level constitutive transcription was observed. In contrast to the results obtained under tissue culture conditions, introduction of the same DNA into the mouse germline resulted in tissue-specific expression of the transgene. We now report identification of a region 500-bp 5' of the human IFN-gamma TATAA box that has strong, PMA-inducible, enhancer-like activity when linked to a reporter gene (CAT) and transfected into a murine T cell line. However, when the same region of IFN-gamma genomic DNA was introduced into NIH-3T3 cells, no enhancer activity was detected either in the presence or absence of PMA. We have further found that an intronic region of the IFN-gamma genomic DNA (nucleotides 405-674) also contains enhancer activity that is functional in either fibroblasts or T cells. Enhancer activity of the intronic region is also PMA-inducible in the mouse T cells but constitutive in fibroblasts. Collectively, our observations suggest that control of human IFN-gamma gene expression is complex, involving noncontiguous regulatory domains in both 5' flanking and intronic regions of that gene.
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PMID:Identification of enhancer-like elements in human IFN-gamma genomic DNA. 210 4

Human retroviruses, such as the HIV, infects human T cells, and efficient HIV replication occurs primarily in activated T cells rather than resting cells. Increased HIV production is likely caused by the activation of the retroviral promoter, and the HIV promoter may be regulated by intracellular signals induced during immune stimulation. To examine the regulation of retroviral promoter activity in normal, Ag-specific primary T lymphoblasts, a heterogeneous population of primary human T cells was transfected with either the HIV promoter or a promoter from a different retrovirus, Rous sarcoma virus (RSV) by protoplast fusion technique. Transfected T cells responded normally to Ag or mitogen stimulation, and activation of these T cells increased both the HIV and RSV promoter activity. Promoter activity was assessed by using transient expression assays after the T cells were restimulated with Ag, mitogen, or IL-2. In situ hybridization of transfected human T cells showed that 68 to 95% of activated lymphocytes expressed CAT mRNA directed by HIV or RSV. Thus, protoplast transfection of primary T cells was efficient in that the majority of cells expressed CAT message. By deletion of different regions of the HIV promoter, the enhancer region was identified as necessary for effective HIV promoter activity. In addition these deletion studies identified a region that negatively affects HIV promoter activity in primary T cells. Cotransfection of the HIV promoter with the HIV transactivator protein, tat, increases HIV promoter activity in both resting and activated primary human T cells only when the tat target sequences were present.
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PMID:HIV promoter activity in primary antigen-specific human T lymphocytes. 247 57

Polyamine biosynthesis by mononuclear cells (MNC) appears to regulate T cell activity since 1) inhibition of polyamine biosynthesis increases IL-2 production and 2) H2O2 (a product of polyamine oxidase, PAO), suppresses lymphocyte proliferation. We investigated this immunoregulatory mechanism and find that catalase, an H2O2 inhibitor, also enhances IL-2 production by MNC. The addition of PAO, but only in the presence of either endogenous or exogenous spermidine (a polyamine), decreases IL-2 production; this effect is catalase inhibitable. Pre-incubation with spermidine, but not any of three diamines tested, suppresses PHA-stimulated IL-2 production and this effect requires monocytes. Three PAO inhibitors have an enhancing effect on IL-2 production which is again monocyte dependent. These results suggest that: 1) H2O2 produced by PHA-activated PBMC down-regulates IL-2 production; 2) products of the interaction between PAO and spermidine inhibit IL-2 production and H2O2 is essential but apparently not sufficient to mediate this effect; 3) human PBMC contain PAO activity. This polyamine-PAO-dependent inhibitory mechanism might constitute a feedback loop that limits human T cell proliferation and, consequently, also the immune responses mediated by these cells.
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PMID:Polyamine oxidation down-regulates IL-2 production by human peripheral blood mononuclear cells. 278 3

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

Activated macrophages are known to release a variety of immunoregulatory substances including the low-molecular-weight substances hydrogen peroxide and lactate. We report here that lactate but not hydrogen peroxide is capable of supporting a substantial production of T-cell growth factor (TCGF) in cultures of accessory cell-depleted splenic T-cell populations after stimulation with concanavalin A. Hydrogen peroxide and its biosynthetic precursor superoxide anion (O2-) mediate, however, a strong augmentation of the TCGF production by accessory cell-depleted T-cell populations in the presence of lactate. Lactate inhibits the incorporation of [3H]thymidine in short-term cultures (18-26 hr) of accessory cell-depleted T cells. This confirms the rule that (optimal) production of T-cell growth factor requires a growth inhibitory signal. Concentrations of hydrogen peroxide which augment TCGF production most effectively (i.e., 1 X 10(-5) M) do not inhibit the incorporation of [3H]thymidine; and higher concentrations (3 X 10(-5)-1 X 10(-4) M) of hydrogen peroxide inhibit both the production of TCGF and the incorporation of [3H]thymidine. In agreement with the augmenting effect of hydrogen peroxide on TCGF production, it was observed that the proliferative response in mixed lymphocyte cultures is suppressed by catalase and augmented by 1 X 10(-5) M H2O2. Proliferative and cytotoxic responses in mixed lymphocyte cultures with an external source of interleukin 2 (IL-2) in contrast, are not augmented by 1 X 10(-5) M H2O2. The relatively high concentration of 1 X 10(-4) M hydrogen peroxide was found to inhibit the proliferative responses in mixed lymphocyte cultures with or without external IL-2 but not the cytotoxic response in the presence of IL-2. This indicates that CTL precursor cells may be relatively resistant against H2O2.
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PMID:Regulation of T-cell activation and T-cell growth factor (TCGF) production by hydrogen peroxide. 304 Feb 70

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

Using a cloned cDNA copy of T-cell growth factor (TCGF) mRNA from the Jurkat leukemic T-cell line, we have isolated three overlapping TCGF genomic clones from a human DNA library. The entire TCGF gene is contained within two adjacent EcoRI fragments spanning about 8 kilobases. The complete nucleic acid sequence was determined. The gene is divided into four exons. The 5' untranslated region and the first 49 amino acids of the protein, 20 of which constitute a signal polypeptide and are not present in the secreted protein, are encoded by the first exon. Exons 2 and 3, separated from each other by a long intervening sequence, contain coding information for the next 20 and 48 amino acids, respectively. The remaining 36 amino acids and the 3' untranslated region are contained in the fourth exon. A promoter sequence T-A-T-A-A-A is present 77 base pairs (bp) upstream from the translation initiation site, and a CAT homology region occurs 104 bp upstream from the initiation site. A putative site for initiation of mRNA transcription was identified 53 bp 5' of the translation initiation codon. The organization of the gene was shown by Southern blot analysis to be identical in normal peripheral blood lymphocytes and in a variety of malignant lymphoid cell types. Restriction analysis of these cellular DNAs produced results exactly as predicted by the map for the cloned genomic TCGF, indicating that there is only a single copy of the human TCGF gene.
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PMID:T-cell growth factor: complete nucleotide sequence and organization of the gene in normal and malignant cells. 660 29

This experiment was from 3 aspects to study the relationship between modulating immune senescence and the improvement of free radical metabolism by the recipe of Baweidankun decoction (BWDKD). The results showed that the production of IL-2 decreased, the content of LPO increased and the activity of catalase (CAT) declined in old mice. After medication of BWDKD the above-mentioned indices were modulated. The ozone inhaled mice revealed similar changes of aging in the above indices. After BWDKD administration, the content of LPO decreased, meanwhile, the activity of CAT and IL-2 were strengthened and showed linear correlation. It was discovered that the production of IL-2 decreased significantly after adding H2O2 into the culture of splenic lymphocytes, but when BWDKD was added simultaneously, the IL-2 production was restored to the level of control group, in which no H2O2 was added. The results suggested that the modulating effect of BWDKD on immune senescence was closely related with the improvement of free radical metabolism, and it provided a partial evidence for the viewpoint of "Vitality deficiency with blood stasis is the principal mechanism of senescence".
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PMID:[Mechanism of tonifying kidney and removing blood stasis recipe in modulation of immune senescence]. 754 87

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

An Il-4 regulatory element, activation responsive element (ARE), located between -88 and -60, contributes to activation-dependent transcription of IL-4/CAT reporter gene constructs in T cells. It was previously demonstrated that nuclear proteins present in both unstimulated and stimulated T cells specifically interact with the ARE. In this study, these proteins were further characterized. UV cross-linking experiments established that multiple proteins are associated with the ARE in both the constitutive and activation-dependent complexes and several of these have identical apparent m.w. The formation of both complexes is dependent on the same ARE subsequence. In addition, activator protein 1 family members are uniquely associated with the activation-dependent complex. These results support a model in which activation-dependent proteins, including jun/fos family members, associate with a preexisting transcription complex to influence inducible IL-4 gene transcription. The ARE shares 9 bp of sequence identity with the IL-2 nuclear factor of activated T cell (NF-AT) binding site within the critical protein binding region, and several features of ARE-protein interactions are similar to the NF-AT transcription complex. However, we demonstrate that the constitutive nuclear ARE-associated factors react with Abs, raised to NF-ATp and NF-ATc, preferentially bind to the ARE but not to the NF-AT binding site and are cyclosporin A sensitive. Taken together, these data indicate that there are IL-4 gene-specific factors associated with the ARE and that the formation of the ARE and NF-AT complexes are regulated differently.
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PMID:Characterization of the constitutive and inducible components of a T cell IL-4 activation responsive element. 772 12


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