Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A multiple immunodeficiency, involving antibody- and cell-mediated responses in 10 Chinese Shar-Pei (CSP) dogs is described. Abnormal levels of serum IgM and IgA in most cases, and IgG in fewer cases characterized the immunoglobulin deficiencies. Decreased in vitro proliferative responses of pokeweed mitogen (PWM)-stimulated peripheral blood mononuclear cells (PBMC) were found in nine cases. Clinical presentation involved several organ systems and was associated with recurrent infections and malignancy. Sera from affected dogs suppressed PWM-stimulated cell proliferation of affected and normal dogs, but not cultures stimulated with PWM followed by recombinant IL-2 (rIL-2). In vitro supplementation of PBMC cultures with immunomodulatory guanosine analogs (GA) resulted in increased de novo IgG and/or interleukin-6 (IL-6) synthesis. Cells from five immunodeficient dogs showed in vitro evidence of GA- or rIL-2-dependent enhanced immunological responses. Since rIL-2-mediated activation of the IL-2 receptor and GA-mediated immunomodulation are reported to act through protein kinase C (PKC)-independent pathways, it is concluded that the IL-2 receptor is functional in these dogs and that cell activation through alternative pathways may restore immune responses in affected CSP dogs.
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PMID:A primary immunodeficiency syndrome in Shar-Pei dogs. 785 14

To determine a role of protein kinase C (PKC) isozymes in lymphocyte activation, human peripheral blood mononuclear cells were activated with 12-deoxyphorbol-13-O-phenylacetate (dPP; an agonist of both calcium-dependent and calcium-independent PKC isozymes), thymeleatoxin (TX; an activator of calcium-dependent PKC alpha, beta, and gamma), and 12-deoxyphorbol-13-O-phenylacetate 20 acetate (dPPA; an activator of PKC beta 1 isozyme) and examined for DNA synthesis, lymphocyte proliferation, interleukin-2 (IL-2) production, expression of IL-2 receptor alpha and beta chains on CD3+, CD4+, and CD8+ T lymphocytes and CD20+ B lymphocytes, and translocation of PKC beta isozyme from cytosol to membrane fraction. The results show that dPPA activates lymphocytes by inducing the above changes in a manner analogous to that of dPP, TX, and phorbol myristate acetate. These data suggest that PKC beta 1 is involved in the activation of human peripheral blood T and B lymphocytes.
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PMID:12-Deoxyphorbol-13-O-phenylacetate 20 acetate [an agonist of protein kinase C beta 1 (PKC beta 1)] induces DNA synthesis, interleukin-2 (IL-2) production, IL-2 receptor alpha-chain (CD25) and beta-chain (CD122) expression, and translocation of PKC beta isozyme in human peripheral blood lymphocytes: evidence for a role of PKC beta 1 in human T cell activation. 792 99

Bryostatin 1 is a protein kinase C activator that inhibits growth of tumour cells and activates lymphocytes in vitro, properties that have encouraged its use in phase 1 clinical studies as an anticancer agent. We investigated interleukin-2(IL-2)-induced proliferation and lymphokine-activated killer (LAK) cell activity in peripheral blood mononuclear cells (PBMC) from cancer patients receiving Bryostatin intravenously. After Bryostatin administration both LAK generation and proliferation were enhanced when patients' PBMC were stimulated with IL-2 in vitro. However, when normal donors' PBMC were cultured in vitro in the presence Bryostatin and IL-2, LAK induction was inhibited while IL-2-driven proliferation was increased. These effects were also seen following only 2 h exposure to Bryostatin and could be elicited by conditioned medium from Bryostatin-pretreated cells. Neither IL-4 nor interferon gamma was detected in the conditioned medium. Bryostatin in vitro was found to increase expression of IL-2 receptors on CD4+, CD8+ and CD56+ cells and augment the proportion of CD8+ cells in conjunction with IL-2. We conclude that Bryostatin in combination with IL-2 in vitro enhances proliferation and IL-2 receptor expression on lymphocytes, favouring CD8+ cells while suppressing the generation of LAK activity. Intravenous administration of Bryostatin increases the potential of IL-2 to induce proliferation and LAK activity in lymphocytes which, taken together with its putative direct antitumour effect, makes Bryostatin an interesting candidate for clinical trials in combination with IL-2.
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PMID:Immunomodulation in patients receiving intravenous Bryostatin 1 in a phase I clinical study: comparison with effects of Bryostatin 1 on lymphocyte function in vitro. 795 24

Soluble proteins of the human immunodeficiency virus (HIV) might play a significant role in the pathogenesis of HIV infection. The addition of synthetic Tat peptides, but not that of the recombinant Nef or Vif protein, inhibited proliferative responses of CD4+ tetanus antigen-specific, exogenous interleukin-2 (IL-2)-independent T-cell clones in a dose-dependent manner. In addition, Tat peptides inhibited the anti-CD3 monoclonal antibody-induced proliferative responses of both purified CD4+ and CD8+ T cells. Tat did not affect proliferative responses induced by phorbol myristate acetate plus ionomycin. The Tat peptides at the concentrations used (0.1 to 3 micrograms/ml) did not affect the viability of the cells as determined by trypan blue exclusion. Treatment of Tat peptides with polyclonal Tat antibodies abrogated the inhibitory effect of Tat. Soluble Tat proteins secreted by HeLa cells transfected with the tat gene also inhibited antigen-induced proliferation of the T-cell clones. Tat inhibited the anti-CD3 monoclonal antibody-induced IL-2 mRNA expression and IL-2 secretion but did not affect IL-2 receptor alpha-chain mRNA or protein expression on peripheral blood T cells. Finally, treatment of T-cell clones with the Tat peptide did not affect the antigen-induced increase in intracellular calcium, hydrolysis of phosphatidyl inositol to inositol trisphosphate, or translocation of protein kinase C from the cytosol to the membrane. These studies demonstrate that the mechanism of the Tat-mediated inhibition of T-cell functions involves a phospholipase C gamma 1-independent pathway.
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PMID:Human immunodeficiency virus Tat induces functional unresponsiveness in T cells. 798 46

The regulation of the interleukin-4 receptor (IL-4R) was studied at mRNA and protein level in monocytic cells on stimulation with activators of different intracellular signaling pathways and IL-4. Activation of protein kinase C-dependent pathways with phorbol myristate acetate (PMA) or activation of protein kinase A-dependent pathways with DBcAMP and prostaglandin E2 resulted in an augmented IL-4R expression at mRNA and protein level. Transcriptional and posttranscriptional mechanisms seemed to be involved in the promotive effect of DBcAMP because the transcription rate increased 1.8-fold, and the half-life of IL-4R mRNA was prolonged to 150 minutes compared with 120 minutes in unstimulated cells. In contrast, the effect of PMA could only be ascribed to changes at transcriptional level. However, activation of Ca(2+)-dependent pathways with A23187 or stimulation with IL-4 had no effect on the IL-4R expression. The unresponsiveness to IL-4 could not be ascribed to a nonfunctional receptor because IL-4 did modulate the CD14, CD23, and HLA-DR antigen expression. These results are in contrast with IL-4R regulation in T cells, which is affected by IL-4- and Ca(2+)-dependent pathways. The discrepancy might be caused by the presence of the common IL-2 receptor gamma chain (gamma c) in T cells and the absence of the gamma c in monocytic cells, as has been shown by polymerase chain reaction. These data indicate that IL-4Rs are differentially regulated, depending on the cell type studied.
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PMID:Interleukin-4 receptor regulation in human monocytic cells. 802 87

The activation of protein kinase C (PKC) is believed to result from the translocation of inactive cytosolic enzyme to the lipid environment of membranes. However, by using a novel method for measuring PKC activity directly in isolated membranes, we have previously shown that a significant proportion of the PKC present in a variety of cells associates with membranes in an inactive state, and that this pool of inactive PKC can be stimulated specifically in cells in the absence of translocation. IL-2 did not stimulate the translocation of PKC to membranes in the IL-2-dependent mouse T cell line, CTLL-2. Nevertheless, a transient, two approximately threefold increase in membrane PKC activity was observed within 10 min of IL-2 addition to these cells. This increase was entirely caused by the activation of a pool of inactive membrane PKC previously associated with the membrane. The inhibition of PKC activity by the specific inhibitors bisindolylmaleimide (BIS) and 1-O-hexadecyl-2-O-methyl-rac-glycerol (AMG) blocked the ability of IL-2 to suppress the onset of apoptosis in IL-2 and serum-deprived CTLL-2 cells. The inhibition of this important function of IL-2 was most pronounced when the PKC inhibitors were added to the medium within 2 h of stimulating the cells with IL-2. The results suggest that transient activation of inactive membrane PKC is linked to the IL-2 receptor signaling, and may be an important step in the mechanism(s) by which the cytokine suppresses cell death in T lymphocytes.
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PMID:Evidence that the activation of an inactive pool of membrane-associated protein kinase C is linked to the IL-2-dependent survival of T lymphocytes. 804 29

Several lines of circumstantial evidence support the assumption that protein kinase C (PKC) activation together with elevated levels of cytosolic Ca++ are necessary for T-cell activation and proliferation in response to a physiological stimulus, i.e., MHC class II restricted antigen presentation. By using a potent, cell-permeable and selective inhibitor of PKC, Ro 32-0432, we have tested this hypothesis. Ro 32-0432 inhibits interleukin-2 (IL-2) secretion, IL-2 receptor expression in, and proliferation of, peripheral human T-cells stimulated with phorbol ester together with phytohemagglutin or anti-CD3, but does not inhibit IL-2 induced proliferation in cells already stimulated to express IL-2 receptors. Proliferation of the influenza peptide antigen HA 307-319-specific human T-cell clone (HA27) after exposure to antigen-pulsed autologous presenting cells was also inhibited by Ro 32-0432. Oral administration of Ro 32-0432 inhibited subsequent phorbol ester-induced edema in rats demonstrating the systemic efficacy of the compound to inhibit PKC-driven responses. Induction of more physiologically T-cell driven responses such as host vs. graft responses and the secondary paw swelling in adjuvant-induced arthritis were also inhibited by Ro 32-0432. These data demonstrate the crucial role for PKC in T-cell activation and that selective p.o. bioavailable PKC inhibitors are efficacious in preventing T-cell driven chronic inflammatory responses in vivo. Inhibition of PKC represents an important mechanistic approach to prevent T-cell activation and compounds of this class may have important therapeutic applicability to chronic inflammatory and autoimmune diseases.
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PMID:Ro 32-0432, a selective and orally active inhibitor of protein kinase C prevents T-cell activation. 811 6

The T cell antigen receptor (TCR) and the interleukin-2 receptor (IL-2R) are important receptors in haematopoiesis since they control the activation and growth of T lymphocytes, respectively. The term T cell activation refers to the events that occur as T cells progress from the G0 to the G1 phase of the cell cycle and is characterised by the production of a wide range of cytokines and other immunomodulators crucial for the growth and development of other haematopoietic cells. Activation also induces the T cells to express on their cell surface high affinity receptors for various cytokines which enable the T cell to respond to the different cytokines generated during an immune response. One well characterised event that occurs when mature T cells are activated is the production of the cytokine IL-2 and the acquisition by the T cell of high affinity IL-2 receptors. Interaction between IL-2 and its cellular receptor than direct T cell growth. One notable difference between TCR and IL-2R signal transduction is that the TCR regulates intracellular calcium and stimulates protein kinase C whereas the IL-2 receptor does not. The present review focuses on TCR and IL-2R regulation of two common intracellular signalling pathways: the regulation of a PtdIns-3-kinase and the activation of the guanine nucleotide binding proteins p21ras. The aim is to illustrate differences in the mechanisms that couple the TCR and IL-2R to these two signalling pathways and attempt to explain the apparent discrepancy of TCR and IL-2R regulation of shared signal transduction pathways even though these receptors mediate quite distinct biological responses.
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PMID:Regulation of PtdIns-3-kinase and the guanine nucleotide binding proteins p21ras during signal transduction by the T cell antigen receptor and the interleukin-2 receptor. 826 Jun 48

In rheumatoid arthritis and other inflammatory diseases we and others have found that gamma delta T cells express activation antigens, suggesting that they are involved in the pathogenesis of these disorders. In this study we have stimulated peripheral blood mononuclear cells from normal donors with recombinant interleukin-2 (rIL-2) to see whether such a stimulus alone could activate gamma delta T cells. Short-term exposure (24-96 h) to rIL-2 selectively stimulated the gamma delta but not the alpha beta T cells to express activation antigens (CD69, CD25 and HLA-DR). Long-term culture (2 weeks) in rIL-2-containing medium caused a selective increase in the proportion of the gamma delta T cells and a corresponding reduction of the fraction of alpha beta T cells. Limiting dilution analysis revealed that approximately 1/60 of the gamma delta T cells responded to IL-2 in contrast to only 1/250 of the alpha beta T cells. Comparison of the expression of the IL-2 receptor (IL-2R) alpha and beta chains showed that there was a similar expression of the alpha chain on gamma delta and alpha beta T cells whereas the relative density of the beta chain was more than twice as high on gamma delta T cells. Both the IL-2-induced proliferation of gamma delta T cells and the expression of activation antigens on these cells could be inhibited by an anti-IL-2R beta monoclonal antibody (mAb) but not by an anti-IL-2R alpha mAb. Expression of CD69 on gamma delta T cells was dependent neither on the presence of B cells, monocytes, nor alpha beta T cells. Finally, we found that the IL-2-induced expression of CD69 was inhibited by activation of cAMP-dependent protein kinase and by inhibition of the Src-family of the tyrosine protein kinase, but not by inhibition of protein kinase C or by activation of the CD45 associated tyrosine phosphatase. The ability of gamma delta T cells to be activated by IL-2 is a feature which they have in common with natural killer cells. Moreover, it may be possible that the expression of activation antigens on gamma delta T cells in inflammatory diseases is an epiphenomenon secondary to IL-2 produced by activated alpha beta T cells.
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PMID:Selective activation of resting human gamma delta T lymphocytes by interleukin-2. 837 Mar 91

Interleukin 2 (IL-2) stimulated activation of the 42-kD extracellular signal-regulated kinase 2 (Erk2) in murine IL-3-dependent cells, expressing either high or intermediate affinity IL-2 receptors. Activation was both rapid, occurring within 5 min of IL-2 addition, and prolonged, remaining elevated for 30 min. Activation of Erk2 appeared to be necessary for IL-2 stimulation of proliferation, as deletion of a region of the cytoplasmic domain of the IL-2 receptor beta chain, essential for IL-2 stimulation of proliferation, abolished Erk2 activation by IL-2. Furthermore, cells that had been deprived of cytokine for 24 h were then refractory to IL-2 stimulation of both Erk2 activity and proliferation. However, elevation of Erk2 activity was not sufficient to stimulate proliferation, as protein kinase C activation stimulated Erk2 activity but not DNA synthesis. Also, cells exposed to IL-2 in the presence of rapamycin showed full Erk2 activation but not DNA synthesis. These data suggest that IL-2 must stimulate both Erk2 activity and a further pathway(s) to trigger cell proliferation.
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PMID:Interleukin 2 activates extracellular signal-regulated protein kinase 2. 837 45


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