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)

Recent studies performed in the laboratory have established that interleukin-4 (IL-4) used in combination with anti-CD40 monoclonal antibody (MoAb) 89 presented on Ltk- mouse fibroblasts stably expressing human Fc gamma RII/CDw32 (referred to as the CD40 system) sustains long-term proliferation of normal human B cells. In the present study, B-cell chronic lymphocytic leukemias (B-CLLs) activated through slgs or CD40 were examined for their capacity to proliferate and differentiate in response to various cytokines. Our results indicate that the outcome of IL-4 stimulation on the in vitro growth of B-CLL depends on the signalling pathway used for their activation. Whereas IL-4 did not display any growth-stimulatory effect on B-CLL activated by Ig cross-linking agents, it could stimulate DNA synthesis and enhance the viable cell recovery when leukemic B cells were cultured in the CD40 system. Most B-CLL samples were induced for IgM synthesis upon Staphylococcus aureus strain Cowan I stimulation. This Ig response was potentiated by IL-2 and antagonized by IL-4. Anti-CD40 MoAb used alone or in combination with cytokines (IL-1 alpha to IL-6, interferon gamma, tumor necrosis factor gamma, and transforming growth factor beta) failed to induce Ig secretion from B-CLL cells. No evidence for Ig isotype switching was obtained with the cytokines listed above, regardless of the mode of activation. Taken together, our results suggest that B-CLL cells can be partially released from their apparent maturation block by IL-2 and Ig cross-linking agents. In contrast, combinations of IL-4 and cross-linked anti-CD40 antibodies induced entry of B-CLL cell into cycle, but poorly stimulated their differentiation into Ig secreting cells.
 ...
PMID:Responsiveness of chronic lymphocytic leukemia B cells activated via surface Igs or CD40 to B-cell tropic factors. 128 92

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.
 ...
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

Activated lymphocytes and malignant lymphoma cells derived from them (Ki-1 positive lymphoma cells) share similar mechanisms of proliferation. To further examine the inhibitory role of endogenous transforming growth factor beta (TGF beta) in Ki-1 positive lymphoma cells, the authors studied anti-TGF beta antibodies and measured their effect on proliferation. A monoclonal antibody (T1A5) prepared against a unique antigenic epitope of high molecular weight Hodgkin's TGF beta and a polyclonal rabbit antibody prepared against highly purified 25,000 D porcine platelet TGF beta 1 were used. Both antibodies are shown here to inhibit the biological activity of Hodgkin's TGF beta and to crossreact with their respective antigens in immunoblotting. DNA synthesis by Ki-1 lymphoma cells was increased 138-fold by anti-TGF beta 1 antibody and 262-fold by anti-Hodgkin's TGF beta. Exogenous TGF beta 1 suppression was completely reversed by anti-TGF beta 1 antibody and IL-2-induced proliferation was markedly potentiated (41 fold). L-428 Reed-Sternberg cells secrete physiologically active TGF beta but have fewer than 500 TGF beta receptor sites per cell; no significant proliferative response was measured for either anti-TGF beta 1 or anti-Hodgkin's TGF beta. These results show the suppressive effect of exogenous TGF beta 1 on indolent Ki-1 lymphoma cells and suggest that the endogenous secretion of high molecular weight physiologically active TGF beta is important in maintaining the indolent nature of this low-grade Ki-1 positive lymphoma.
 ...
PMID:Neutralizing antibodies against transforming growth factor beta potentiate the proliferation of Ki-1 positive lymphoma cells. Further evidence for negative autocrine regulation by transforming growth factor beta. 131 8

T lymphocytes can be induced to produce interleukin (IL)-2 and proliferate upon T cell receptor (TcR) occupancy together with a CD28-induced co-stimulatory signal. The T cell surface molecule CD28 is believed to function as a regulator in T cell activation at both the level of lymphokine mRNA stabilization and gene transcription. Activation of IL-2 gene transcription via CD28 has been shown to be mediated through a kappa B-like sequence, called CD28RE. DNA binding analysis revealed that the CD28-induced signal is involved in the induction of CD28RE binding activity. Here, we demonstrate that the induction of CD28RE binding activity is not specific for the CD28-induced signal. Our data indicate that distinct mitogenic T cell activation signals converge on the induction of CD28RE binding activity, and suggest a crucial role for this activity in the IL-2 enhancer responsiveness to different modes of T cell activation.
 ...
PMID:Evidence for a role of CD28RE as a response element for distinct mitogenic T cell activation signals. 133 May 79

To define membrane-associated molecules that impart signals for the activation and expansion of double negative (DN) cells, mAb were raised against in vitro-cultured rat DN cells. One such mAb, 1.3, stimulated proliferation of DN cells along with submitogenic concentrations of PMA and IL-2 without affecting the mobilization of Ca2+. The 1.3 mAb precipitated a heterodimeric protein from DN cells and kidney (130/110 kDa). Although the tissue distribution and biochemical characteristics of the 1.3 determinant resemble the neutral aminopeptidase (AP-N) first described as the thymocyte activating molecule in the mouse, other data are contradictory; AP-N message was not detected in mRNA from 1.3 positive cells and the AP-N gene was absent in the genomic DNA from rat DN hybridomas expressing high levels of 1.3 Ag. In addition, the 1.3 mAb did not affect AP-N enzyme activity suggesting that 1.3 mAb does not function through this enzyme to transduce signals for proliferation. Thus, the 1.3 mAb defines a new and important thymocyte costimulating Ag.
 ...
PMID:Characterization of a novel rat thymocyte costimulating antigen by the monoclonal antibody 1.3. 134 19

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.
 ...
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

The ability of purified T cells to be activated by immobilized anti-CD3 and soluble anti-CD2 monoclonal antibodies (mAbs) was compared using cells from young and old donors. Purified T cells from elderly humans activated with immobilized anti-CD3 mAb incorporated less [3H]thymidine (58,780 vs 92,258 cpm; p < 0.02) into cellular DNA, and secreted less IL-2 into the culture supernatants than did T cells from young donors. In contrast, T cells activated with anti-CD2 mAbs displayed no age-related differences in proliferation or IL-2 production. Anti-CD2 stimulation resulted in equal IL-2 synthesis by cells from young and old donors that was comparable to the amount produced by cells from elderly donors stimulated with immobilized anti-CD3. Northern blot analysis of early cell cycle gene expression by anti-CD2 activated T cells demonstrated no age differences in the expression of p55 IL-2R or c-myc specific mRNA, although T cells from elderly individuals activated with immobilized anti-CD3 showed statistically significant decreases in both mRNAs. T cell receptor beta chain mRNA levels did not differ between cells from young or old donors after activation by either anti-CD3 or anti-CD2. The discordance in proliferative ability, IL-2 secretion, and specific mRNA expression between T cells from elderly donors activated through the CD3-TCR complex or by soluble anti-CD2 mAbs provides additional evidence for a multifactorial causation of age-related T cell proliferative defects, and may indicate that the difference in proliferative ability is, in part, attributable to responsiveness to secreted IL-2.
 ...
PMID:Comparison of CD3 and CD2 activation pathways in T cells from young and elderly adults. 136 63

Fas is a mouse monoclonal antibody-defined cell surface antigen of an unknown physiologic function. Previous studies demonstrated that the anti-Fas antibody mediated apoptosis in those cells sensitive to tumor necrosis factor (TNF) and, further, triggered the co-downregulation of tumor necrosis factor receptors (TNF-Rs). These findings led to speculation that Fas may be associated with TNF-Rs. The present studies were undertaken as an extension of our previous work on the obligate requirement for TNF in development and maintenance of cytotoxic lymphocytes and were designed to analyze the expression and consequences of Fas engagement in these cells. Herein, we demonstrate that, in contrast to TNF-R expression, both resting and IL-2-activated lymphocytes express Fas. In accordance with previous studies using tumor cell lines, lymphocytes rapidly downregulate TNF-Rs after treatment with anti-Fas. The ability of anti-Fas to mediate apoptotic cell death in lymphocytes, however, was dependent upon the status of cellular activation. For example, lymphocytes activated in IL-2 for longer than 4 days underwent rapid DNA fragmentation and cell death after anti-Fas treatment. Despite their expression of Fas, nonactivated lymphocytes and those activated for periods less than 4 days were refractory to antibody-mediated cell killing. Because anti-Fas-mediated lethality is selective for chronically activated lymphocytes, Fas may prove to be an appropriate target for immunosuppressive intervention.
 ...
PMID:DNA fragmentation and cell death is selectively triggered in activated human lymphocytes by Fas antigen engagement. 137 Dec 42

After the initial stages of activation, T cells are not able to proliferate on their own but become competent to proliferate in response to exogenously added lymphokines. In the present study we compared the capacity of mAb directed to CD3 (OKT3, Leu4, UCHT1) or to common epitopes on the alpha/beta T-cell receptor (BMA 031, BMA 032) to induce competence in purified resting T cells. Stimulation with either soluble anti-CD3 or anti-alpha/beta TCR mAb rendered cells competent to progress to DNA synthesis in response to exogenous IL-2. In contrast, only soluble BMA 031 and BMA 032 were able to induce responsiveness to IL-4; anti-CD3 mAb had either to be immobilized or used in combination with anti-CD28 mAb to induce responsiveness to IL-4. Further, BMA 031-induced IL-4 responsiveness was selectively found in the CD45RA+ T cell subset. Analysis of early activation events revealed that the capacity of soluble BMA 031 and BMA 032 to induce responsiveness to IL-4 did not correlate with the ability of these mAb to increase the level of cytosolic Ca2+ or to induce detectable tyrosine phosphorylation. On the other hand, soluble Leu4 (anti-CD3) triggered an increase in both intracellular Ca2+ and tyrosine phosphorylation but was unable to induce IL-4 responsiveness. These data indicate that the induction of IL-2 and IL-4 responsiveness requires different sets of activation signals which can be induced by stimulating different epitopes in the CD3-TCR complex. This supports the concept that distinct activation pathways are coupled to the CD3-TCR complex.
 ...
PMID:Monoclonal antibodies directed to different epitopes in the CD3-TCR complex induce different states of competence in resting human T cells. 137 24

Human gamma-globulin (HGG)-specific mouse Th1 clones exposed to tolerogenic signals provided by HGG-pulsed paraformaldehyde-fixed splenocytes (HGG-FAPC) were analyzed for antigen-induced progression through the early phases of the cell cycle. Exposure of Th1 clones to HGG-FAPC in primary cultures inhibits the ability of the clones to synthesize DNA in response to HGG and normal APC in secondary cultures. The Th1 clones in these secondary cultures were found to be blocked in G1a phase as evidenced by cell cycle analysis and by reduced numbers of cells expressing high levels of IL-2R and TfR. This cell cycle blockade of Th1 cells was not observed if the secondary cultures were stimulated with IL-2-containing Con A CM instead of antigen. These data suggest that in our system the inhibition in antigen-induced cell cycle progression associated with Th1 tolerance induction occurs at the G1a/G1b phase transition.
 ...
PMID:Effects of tolerance induction on early cell cycle progression by Th1 clones. 137 89


1 2 3 4 5 6 7 8 9 10 Next >>