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)

Recently, the SRC-like non-receptor protein tyrosine kinase p56-LCK has been shown to physically associate with the interleukin-2 receptor (IL-2-R) complex and to undergo rapid elevations in its tyrosine kinase activity upon stimulation of T lymphocytes with IL-2. The functional significance of p56-LCK kinase activation for IL-2-mediated lymphocyte responses, however, has never been directly assessed. Using gene transfer approaches, we have achieved markedly elevated levels of p56-LCK kinase activity in the IL-2-dependent cytolytic T-cell line CTLL-2 and the helper line HT-2. CTLL-2 and HT-2 cells that were stably transfected with expression plasmids encoding either the normal human p56-LCK or a constitutively active version of the mouse p56-LCK kinase (LCK[Y505]) contained striking elevations in the levels of tyrosine phosphorylation on several proteins (34-36, 50-60, 62-68, 77-78, 104-110 kDa), as determined by immunoblot analysis using anti-phosphotyrosine antibodies. CTLL-2 and HT-2 LCK- and LCK(Y505F)-transfected cells remained dependent on IL-2 for their growth and survival in culture despite the findings that (i) IL-2 specifically stimulated elevations in the activity of the endogenous p56-LCK in untransfected CTLL-2 cells without affecting the activities of the other SRC-like kinases in these cells (p59-FYN, p62-YES) and that (ii) IL-2-mediated regulation of p56-LCK correlated with IL-2-driven proliferation of these T cells. Specifically, no elevation in the proliferation (DNA synthesis) or growth of these T cells was found at any of the concentrations of IL-2 examined (0.01-25 U/ml), relative to untransfected and control transfected cells. Furthermore, when cultured in the absence of IL-2, transfected T cells whose relative levels of p56-LCK activity were elevated by approximately 20-50-fold died with the same kinetics as control cells and underwent apoptosis, as defined by uptake of trypan blue dye and DNA fragmentation assays, respectively. Taken together, these data indicate that while IL-2 can up-regulate the enzymatic activity of p56-LCK, elevated levels of p56-LCK tyrosine kinase activity are insufficient to stimulate IL-2-mediated pathways required for T-cell growth and survival. These findings thus imply the existence of other signal-transducing molecules, besides p56-LCK, that physically participate in IL-2R complexes and that are necessary for initiation of the biochemical events ultimately responsible for IL-2's pleiotropic actions on lymphocytes.
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PMID:Gene transfer investigations of p56-LCK function in IL-2-dependent T-cell lines: implications for mechanisms of IL-2-signal transduction. 129 28

We report that a human CD4+ T cell clone with specificity for staphylococcal enterotoxin (SE) superantigens A, D, and E can respond to SEs in two seemingly opposite ways. In the absence of antigen presenting cells (APC), SEA, D, and E (but not SEB or C1) strongly inhibited in a dose-dependent manner the responsiveness of clone D894/25 to exogenous IL-2. Growth inhibition was due to SE-induced programmed cell death (apoptosis) as shown by propidium iodide staining and the appearance of the characteristic ladder pattern of DNA fragmentation. Apoptotic cell death was accompanied by significant cell lysis after 4 and 8 h as measured in a 51Cr release assay. In contrast (but as expected), a proliferative response of clone D894/25 was triggered by SEA, D, and E in the absence of exogenous IL-2 but presence of HLA class II-positive lymphoblastoid cell line (LCL) as APC. Moreover, the addition of LCL feeder cells partially prevented the suppression of IL-2 responsiveness by SEs. Surprisingly, however, the latter two culture conditions (i.e. presence of LCL feeder cells with or without exogenous IL-2) were associated with similar levels of induced cell death as in the absence of LCL. At the clonal level, these data demonstrate that SE superantigens induce programmed cell death in a fraction (40-50%) of responsive mature T cells, irrespective of the presence or absence of MHC class II-positive APC. We conclude that the proliferative response of clone D894/25 which is triggered by SEs in the presence of APC and absence of IL-2 must originate from the fraction (50-60%) of clone T cells surviving SE-induced cell death.
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PMID:Life and death of a superantigen-reactive human CD4+ T cell clone: staphylococcal enterotoxins induce death by apoptosis but simultaneously trigger a proliferative response in the presence of HLA-DR+ antigen-presenting cells. 136 55

Peptide growth factors are proteins that stimulate cellular proliferation by binding to specific cell membrane receptors. Evidence is accumulating that abnormal regulation of growth factors may contribute to carcinogenesis. The epithelial growth factors, EGF and TGF-alpha, which share the same receptor, EGFR, may play a pivotal role in the development and maintenance of head and neck cancer; preliminary studies concerning TGF-beta and IL-2 are inconclusive. There is increased production of TGF-alpha and EGFR mRNA in the majority of fresh tissues and cell lines from patients with SCCHN. This increase results from transcriptional activation of the gene(s). Therapies directed at the regulation of gene transcription may be useful in chemoprevention or modulation of disease. Nuclear studies that target up-regulated growth factor receptors may improve the ability to detect microscopic regional metastatic disease.
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PMID:The role of peptide growth factors in head and neck carcinoma. 140 94

Genes homologous to those located on human chromosome 4 (HSA4) were mapped in the bovine to determine regions of syntenic conservation among humans, mice, and cattle. Previous studies have shown that two homologs of genes on HSA4, PGM2 and PEPS, are located in bovine syntenic group U15 (chromosome 6). The homologous mouse genes, Pgm-1 and Pep-7, are on MMU5. Using a panel of bovine x hamster hybrid somatic cells, we have assigned homologs of 11 additional HSA4 loci to their respective bovine syntenic groups. D4S43, D4S10, QDPR, IGJ, ADH2, KIT, and IF were assigned to syntenic group U15. This syntenic arrangement is not conserved in the mouse, where D4s43, D4s10, Qdpr, and Igj are on MMU5 while Adh-2 is on MMU3. IL-2, FGB, FGG, and F11, which also reside on MMU3, were assigned to bovine syntenic group U23. These data suggest that breaks and/or fusions of ancestral chromosomes carrying these genes occurred at different places during the evolution of humans, cattle, and mice.
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PMID:Synteny mapping in the bovine: genes from human chromosome 4. 142 20

IL-2 is one of the principal growth factors regulating the proliferation of T lymphocytes. Although two independent IL-2-binding molecules have been molecularly cloned and shown to participate in the formation of a high affinity receptor complex, their primary structures do not suggest a specific mechanism for IL-2 growth signal transduction across the cell membrane. Neither IL-2 receptor subunit contains an intrinsic kinase domain; nevertheless, tyrosine phosphorylation of various intracellular substrates is one of the first biochemical changes observed following activation of the IL-2 receptor (IL-2R). Both serine/threonine and tyrosine kinases can be co-precipitated as part of the IL-2R complex suggesting that the IL-2 signalling may involve the activation of non-covalently associated intracellular kinases. However, controversy exists as to which kinases are involved in IL-2 signal transduction; in particular, which kinase(s) mediates the first or proximal event(s) in the signalling process. Activation of the IL-2R leads to serine and threonine phosphorylation of the SRC tyrosine kinase family member, LCK, and an increase in LCK tyrosine kinase activity. Furthermore, LCK can be co-immunoprecipitated with the beta chain of the IL-2R indicating its association with the receptor complex. IL-2 has also been reported to increase FYN kinase activity and to alter its association with the 85 kDa subunit of phosphatidylinositol-3 kinase thus suggesting a role for FYN in IL-2 signal transduction. However, in this report, we now demonstrate that neither LCK nor FYN are obligatory for IL-2-induced growth of HTLV-I-infected human T cells. Lack of expression of LCK or FYN in the HTLV-I-infected T cell lines was demonstrated by a combination of Northern blotting, polymerase chain reaction, Western blotting, and in vitro kinase activity. Despite the absence of LCK or FYN, IL-2 induced similar patterns of rapid tyrosine phosphorylation. Similar results were observed in cell lines lacking expression of the LYN, FGR, HCK, and LTK tyrosine kinases. Thus, none of these tyrosine kinases alone appears to be required for growth signalling through the IL-2R in the HTLV-I-infected T cell lines analyzed. The findings raise the possibility that an, as yet, unidentified tyrosine kinase is involved. Alternatively, this biological signalling system may exhibit remarkable redundancy whereby several different tyrosine kinases may be capable of associating with the IL-2R complex and mediating intracellular signalling.
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PMID:Neither the LCK nor the FYN kinases are obligatory for IL-2-mediated signal transduction in HTLV-I-infected human T cells. 147 76

The capacity of staphylococcal enterotoxins to stimulate all T cells bearing certain TCR variable region alleles has generated a great deal of interest. This stimulation appears to involve specific binding of the toxin to class II molecules and subsequent stimulation of the T cell via the TCR V beta elements. Recent studies from our laboratory have focused on the ability of staphylococcal enterotoxins to directly activate purified lymph node T cells and a panel of T cell clones and hybridomas. A T cell costimulation assay was performed to assess cellular activation requirements and cytokine receptor expression. Activation of highly purified lymph node T cells by staphylococcal enterotoxin B (SEB) required costimulatory signals which could be provided by IL-1, IL-2, IL-4, or IL-6, whereas SEB alone demonstrated no significant proliferative response. Using a panel of TH1 and TH2 cell clones and T cell hybridomas possessing various responsive and nonresponsive V beta alleles, it was possible to demonstrate that SEA and SEB costimulate T cells via the TCR complex. Additionally, enterotoxin-pretreated T cells demonstrated a significant proliferative response upon exposure to class II-bearing accessory cells, suggesting that these toxins bind directly to T cells. Highly purified T cells cultured with both SEB and IL-1 exhibit significantly increased levels of IL-2 receptor, whereas cells cultured with SEB or IL-1 alone demonstrated low levels of this receptor. These results do not exclude an association of the staphylococcal enterotoxins with class II molecules in a manner which results in a high avidity binding to the TCR required for transduction of the appropriate activation signals. In the absence of class II molecules, however, these superantigens can still bind to T cells, and the activation signal is delivered in the presence of cytokines that trigger T cell growth and lymphokine production.
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PMID:Direct activation of murine T cells by staphylococcal enterotoxins. 154 63

Human umbilical vascular endothelial cells (HUVEC) express HLA class II molecules upon stimulation with recombinant human interferon-gamma (IFN-gamma). Staphylococcal enterotoxin (SE) A (SEA)-binding assay using [125I]-SEA showed the presence of specific SEA binding in HUVEC stimulated with IFN-gamma but not in unstimulated HUVEC. Levels of HLA class II expression and SEA-binding increased as the IFN-gamma concentration and the period of stimulation were increased. Binding of [125I]-SEA to the IFN-gamma-stimulated HUVEC was reduced markedly by an anti-DR/DP MoAb. T cells produced IL-2 upon stimulation with a group of SEs (SEA, SEB, SEC, SED and SEE) in the presence HUVEC stimulated with IFN-gamma but not in the presence of control HUVEC. The level of accessory cell activity in the IFN-gamma-stimulated HUVEC was related to the level of HLA class II expression and SEA-binding activity. Antibodies to HLA class II molecules almost completely inhibited the response. These results indicate that HLA class II molecules are directly involved in the acquisition of these activities in HUVEC.
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PMID:Involvement of HLA class II molecules in acquisition of staphylococcal enterotoxin A-binding activity and accessory cell activity in activation of human T cells by related toxins in vascular endothelial cells. 173 96

In this study we describe an in situ hybridization protocol suitable for the measurement of interleukin mRNAs in small numbers of cells in suspension. In this procedure defined numbers of such cells are coated onto defined areas of microscopic slides using LAB-TEK tissue culture chamber slides. 32P-labelled oligonucleotides are then hybridized to them in situ. Binding of the probes is measured by autoradiography using X ray film followed by densitometry (slide blot) or, as in standard in situ protocols, by exposure to photoemulsion. In experiments designed to demonstrate the specificity and feasability of this protocol, peripheral blood T cells were activated with mitogenic stimuli and oligonucleotide probes specific for IL-2, IFN-gamma, or a control probe (IL-2 random) were hybridized to them. Both lymphokine genes were found to be transcribed in two discrete phases with the first peak at 12 h and another peak 48 h after stimulation, as measured semi-quantitatively on a per cell basis using X ray film exposure. The proposed experimental protocol supports the advantages of X ray film autoradiography such as rapidity, simplicity and the objectivity of densitometric evaluation, but also permits microscopic evaluation of individual cells as performed in classical in situ hybridization protocols using photoemulsion.
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PMID:A simple and rapid slide blot method to quantify cytokine-mRNA in small numbers of lymphocytes. 176 64

There is now convincing evidence for the imposition of self tolerance by means of the clonal deletion of self-reactive T cells operating within the thymus. Since not all self components may be encountered there, the question must be asked whether tolerance can occur post-thymically. To test this, we and other investigators have used transgenic technology to direct expression of a known "nonself" gene to a given extrathymic tissue. No lymphocytic infiltration was ever seen in transgene-expressing tissues, even if the mice were given normal syngeneic (nontransgenic) spleen cells intravenously or were stimulated with H-2Kb spleen cells. Infiltration did, however, occur in irradiated transgenic recipients of H-2Kb immune spleen cells. In MET-Kb mice, this infiltrate diminished with time, raising the possibility that peripheral tolerance may even have been induced in immune cells. H-2Kb-bearing skin was accepted in young RIP-Kb mice but rejected in older mice, which had lost more than 75% of their beta cells as a result of the overexpression of H-2Kb. This loss of tolerance thus occurred when the concentration of the tolerogen, H-2Kb, fell below some critical threshold. Following in vitro stimulation, spleen cells from young RIP-Kb mice could not kill H-2Kb-bearing targets, but could respond to third party targets. Thymus cells, on the other hand, could be stimulated to kill both targets, clearly indicating that tolerance was not imposed intrathymically. Spleen cells from older RIP-Kb mice (those that had lost most of their beta cells) killed both targets, which is in agreement with the in vivo data. Reactivity to H-2Kb was restored to young spleen cells by providing them with IL-2. Two hypotheses were proposed to account for the above findings: tolerance results either from the deletion or functional silencing of high-affinity effector cells or of regulatory, IL-2-producing helper T cells. As it is difficult to distinguish between these, we have produced a second series of transgenic mice (F3+) with rearranged TCR genes encoding an anti-H-2Kb TCR and derived "double-transgenic" (F3+RIP+) offspring by mating these mice with RIP-Kb mice. The transgenic TCR utilized the V beta 11 segment which can be detected by a monoclonal antibody. There were in the thymus very few CD4+ and very few CD4+8+ cells in both F3+ and F3+RIP+ mice and, in the double-transgenic mice, there was no evidence of deletion of CD8+V beta 11+ cells in the periphery although they showed tolerance to H-2Kb-bearing skin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A transgenic approach to the study of peripheral T-cell tolerance. 193 38

The T cell antigen receptor (TCR) is a multisubunit surface molecule on T cells which recognizes foreign antigens. In addition to the clone-specific alpha beta or gamma delta heterodimer antigen recognition element, each TCR has five invariant chains--the CD3-gamma, -delta, and -epsilon chains and a zeta zeta or zeta eta disulfide dimer. Receptor assembly and surface expression requires the presence of all chains except eta. Targetting of partial complexes, however, is determined differently by specific chains with the zeta chain in murine T cells providing safe transport of assembled pentamers from the Golgi complex to the cell surface. TCR signalling involves activation of two kinase pathways--protein kinase C and a non-receptor protein tyrosine kinase. zeta eta-containing TCRs couple preferentially to the PKC pathway by mediating phosphoinositide hydrolysis. We have evidence that the activated protein tyrosine kinase may be fyn, a member of the src family. While specific signalling roles for all invariant chains are not yet defined, we have implicated the zeta chain as uniquely coupling TCR antigen engagement to distal IL-2 signalling, perhaps via activation of the tyrosine kinase pathway.
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PMID:The structure and signalling functions of the invariant T cell receptor components. 215 1


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