Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of the T3/antigen receptor complex is summarized by the diagram presented in Figure 4. Signals transmitted through T3/Ti activate a phosphodiesterase. This enzyme acts on its substrate PIP2 to generate two important mediators, IP3 and diacylglycerol. IP3 mobilizes calcium from bound intracellular stones. This increase in [Ca2+]i is one intracellular signal which, in conjunction with others, induces expression of lymphokine genes by influencing pretranslational, presumably transcriptional, events. Several problems remain. Which of the five molecules in the T3/Ti complex serves as the effector molecule in the transmembrane signaling process is not known. Which molecules serve to link T3/Ti to the phosphodiesterase enzyme is under investigation. The role diacylglycerol protein kinase C and other mediators play in signalling activation is not established. Finally, for those events occurring after the early events pictured in Figure 4 that result in gene activation, the sequence is a black box. Approaches to address each of these questions are available, and answers should be forthcoming.
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PMID:The role of the T3/antigen receptor complex in T-cell activation. 293 58

When L3T4+ cloned murine helper T lymphocytes (HTL) are stimulated with antigen or immobilized anti-T cell receptor (TCR) monoclonal antibodies (mAb) at concentrations which are optimal for proliferation, anti-L3T4 mAb inhibits activation as measured by proliferation and lymphokine production. Under similar conditions, IL 2-independent proliferation of Lyt-2+ cloned murine cytolytic T lymphocytes (CTL) stimulated by anti-TCR mAb is inhibited by anti-Lyt-2 antibodies. Proliferation of cloned HTL and CTL cells stimulated by IL 2 is not affected by the anti-L3T4 and anti-Lyt-2 mAb. The inhibition of TCR-induced activation of the T cell clones is not due to interference with the binding of the anti-TCR mAb. Stimulation of the TCR has been proposed to induce lymphokine secretion and proliferation by T cells through a pathway involving the activation of protein kinase C and the stimulation of an increase in the concentration of intracellular free calcium. However, proliferation of T cells stimulated by PMA (which activates protein kinase C) plus the calcium ionophore A23187 (which increases the concentration of intracellular free calcium) is not affected by mAb reactive with the Lyt-2 or L3T4 structures. If TCR stimulation does indeed activate T cells by activating protein kinase and increasing intracellular free calcium, then our data suggest that anti-L3T4 and anti-Lyt-2 mAb inhibit TCR-driven proliferation at some step before the activation of protein kinase C and the stimulation of a rise in intracellular free calcium concentration. Our results suggest that anti-L3T4 and anti-Lyt-2 mAb interfere with early biochemical processes induced by stimulation of the TCR. In HTL, which proliferate via an autocrine pathway, anti-L3T4 mAb appears to inhibit proliferation by interfering with signaling events involved in lymphokine production. Inhibition of IL 2-independent proliferation of Lyt-2+ cells by anti-Lyt-2 mAb appears to occur by a different mechanism. The precise molecular basis for the interference of each cell type has not yet been characterized.
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PMID:Antibodies to the L3T4 and Lyt-2 molecules interfere with antigen receptor-driven activation of cloned murine T cells. 295 46

To further characterize the mechanisms responsible for defective interleukin-2 (IL-2) production in patients with systemic lupus erythematosus (SLE), we studied the effect of irradiation on the capacity of lymphocytes to produce this lymphokine when stimulated with phytohemagglutinin (PHA), or with a combination of PHA and a phorbol myristic acid ester (PMA). Irradiation increased PHA induced IL-2 production in patients with SLE and normal controls, and reached normal levels in 10 of 16 patients with SLE. This effect was due to inactivation of CD8+ suppressor cells. When PMA was used as a costimulant, maximal enhancement of IL-2 production was observed in both groups, but values in SLE remained significantly lower than in normals. These differences were not overcome by irradiation, raising the possibility that SLE suppressor cells act upon a site proximal to protein kinase C. Our studies have confirmed that active endogenous suppression may be responsible for most of the defective PHA induced IL-2 production in SLE and that this suppression is radiosensitive.
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PMID:Further characterization of interleukin-2 production by lymphocytes of patients with systemic lupus erythematosus. 297 35

We have investigated the effect of 8-Br-cyclic adenosine 3':5' monophosphate (cAMP), a pharmacological activator of cAMP-dependent protein kinase, on the proliferation and the nuclear proto-oncogene induction in a murine granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent myeloid cell line. Cells were growth arrested by granulocyte macrophage colony-stimulating factor and serum deprivation and were allowed to proceed in the cell cycle by addition of the lymphokine in the presence or absence of 8-Br-cAMP. 3H-thymidine incorporation assays showed that addition of 8-Br-cAMP inhibited the entry of cells into S phase and the subsequent proliferation. Northern analysis showed that 8-Br-cAMP had opposite effects on c-fos and c-myc mRNA induction. 8-Br-cAMP induced c-fos in the absence of any GM-CSF. In the presence of GM-CSF, c-fos mRNA was superinduced (30-fold induction compared to four- to fivefold by each signal alone). On the contrary, 8-Br-cAMP was not able to induce c-myc in the absence of growth factor and hardly interfered with the induction of c-myc by GM-CSF. Phorbol myristate acetate (PMA), a pharmacological activator of the lipid and CA++-dependent protein kinase C, was shown to induce nuclear proto-oncogene mRNA in the GM-CSF-dependent cell line. We investigated the effect of 8-Br-cAMP on PMA-induced c-fos and c-myc mRNA levels. When both cAMP dependent and lipid-dependent kinase systems were co-stimulated in the absence of GM-CSF, c-fos message was again superinduced (60-fold induction). On the contrary, c-myc message induction by PMA was inhibited by 80% by coactivation of cAMP-dependent protein kinase with 8-Br-cAMP. Our data indicate that an antiproliferative signal induces or even superinduces c-fos message and hardly interferes with c-myc induction, suggesting that the intracellular pathways resulting in c-fos and c-myc induction may be distinct and that two different pathways can lead to c-fos induction, with synergistic effects when both are activated.
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PMID:Regulation of proliferation in a murine colony-stimulating factor-dependent myeloid cell line: superinduction of c-fos by the growth inhibitor 8-Br-cyclic adenosine 3':5' monophosphate. 306 31

In vitro immortalized cell lines with the morphology and phenotype of mature macrophages (M phi) have been generated by infecting freshly isolated bone marrow cells from C3H/HeJ mice with a recombinant retrovirus carrying v-raf and v-myc oncogenes. All of the clones obtained had M phi-like phenotypes, and one such clone, GG2EE, has been compared to normal M phi to ascertain the effects of immortalization on the expression of the biological functions of the lines. GG2EE cells expressed cytotoxic activity against L5178Y, P815 or RL male 1 target cells in response to stimulation with interferon-gamma (IFN-gamma) and heat-killed Listeria monocytogenes; in contrast, they failed to kill YAC-1 target cells. GG2EE cells did not constitutively express I-A or I-E antigens; nevertheless, I region-coded antigens could be induced by IFN-gamma treatment. GG2EE cells produced interleukin 1 upon stimulation with a T cell-derived lymphokine; they were weakly phagocytic, yet became highly phagocytic following IFN-gamma treatment. Since c-fos mRNA is augmented in peritoneal exudate M phi by protein kinase C activators but not by IFN-gamma, we evaluated the effects of calcium ionophore, phorbol myristate acetate, L-alpha-1-oleoyl-2-acetoyl-sn-3 glycerol (OAG) and IFN-gamma on the levels of c-fos mRNA in GG2EE cells. We found that calcium ionophore, PMA and OAG stimulation enhanced the expression of c-fos mRNA, but IFN-gamma treatment did not. The kinetics of c-fos induction in GG2EE cells were also comparable to those observed in peritoneal exudate M phi. Overall, the GG2EE cell line has the same biological properties as normal tissue M phi. Because it is capable of both constitutive and inducible M phi-like functions, this cell line provides a valuable tool for studying the molecular mechanisms controlling induction and/or expression of biological activities in M phi. It is striking that a cell line immortalized in vitro by two oncogenes, v-raf and v-myc, behaves, according to the criteria mentioned above, like a normal M phi population.
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PMID:A murine macrophage cell line, immortalized by v-raf and v-myc oncogenes, exhibits normal macrophage functions. 311 52

Interferon-gamma (IFN-gamma) regulates a variety of biological functions and is the principal lymphokine known to activate macrophages. In studies of the molecular mechanisms by which these cells are regulated by IFN-gamma, the transcriptional activation of an IFN-gamma-inducible gene, gamma.1, in human macrophage-like cell lines was examined. Transcription of this gene is rapidly induced by 0.1-1 unit of IFN-gamma. In addition, gamma.1 transcription is efficiently induced by phorbol 12-myristate 13-acetate, which is known to activate protein kinase C (PKC). Both stimulators of gamma.1 transcription induce the translocation of PKC from the cytosol of a membrane fraction. Two selective inhibitors of PKC, H7 and sphingosine, suppressed not only the induction of gamma.1 mRNA but transcription of HLA-DR by IFN-gamma as well. These findings establish that PKC plays a significant role in the signal transduction pathway leading to transcriptional activation of some IFN-gamma-regulated genes of cells of the mononuclear phagocyte lineage.
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PMID:Interferon-gamma-induced transcriptional activation is mediated by protein kinase C. 313 57

We have previously shown that recombinant murine interferon-gamma, rIFN-gamma, and recombinant human interleukin-1 alpha, rIL-1 alpha, induce differentiation of murine pre-B-like cell line 70Z/3, a finding associated with stimulation of Na+/H+ exchange across the plasma membrane. The present study was designed to test whether the enhanced Na+/H+ exchange is mediated by Ca2+/phospholipid-dependent protein kinase C. The results show that two structurally different peptides, rIFN-gamma and rIL-1 alpha, induce identical patterns of transient translocation of protein kinase C from the cytosol to the membranes. The increase in membrane-associated protein kinase C activity was first detected 20 min after exposure to the lymphokines. This activity peaked at 30 min and was back to baseline by 2 h. At each time point, the increase in membrane-associated protein kinase C activity corresponded to a decrease in the activity of protein kinase C in the cytoplasmic fraction. The total cellular activity (cytosol + membrane) remained the same. Two series of experiments were carried out to test the role of protein kinase C in mediating the lymphokine-stimulated Na+/H+ exchange. In the first, the effects of rIFN-gamma and rIL-1 alpha on cytoplasmic pH were measured in the presence of a protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, H-7. In the second, rIFN-gamma- and rIL-1 alpha-induced cytoplasmic alkalinization was determined in cells containing decreased protein kinase C activity. Under both experimental conditions, lymphokine-induced cytoplasmic alkalinization was not attenuated. These results indicate that, although both rIFN-gamma and rIL-1 alpha cause association of protein kinase C with membranes, activation of protein kinase C is not required for rIFN-gamma or rIL-1 alpha to stimulate Na+/H+ exchange across the plasma membrane.
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PMID:Interferon-gamma and interleukin-1 alpha induce transient translocation of protein kinase C activity to membranes in a B lymphoid cell line. Evidence for a protein kinase C-independent pathway in lymphokine-induced cytoplasmic alkalinization. 313 39

Interleukin-2 (IL-2) is a chemically defined lymphokine (LK) available as mixed human (LK) preparations, as partially purified lymphoblastoid IL-2, or as recombinant human IL-2. Each has different actions dependent on companion LKs showing synergistic interaction (e.g., IL-1 and gamma-interferon (gamma-IFN]). IL-2 acts to expand activated T cells; to activate natural killer (NK) cells, lymphokine-activated killer (LAK) cells, and cytolytic T cells (CTL); to regulate T-cell ontogeny via actions on prothymocytes and immature T cells; and to induce gamma-IFN and activate tumoricidal macrophages. IL-2 acts via specific cell surface receptors on protein kinase C and cyclic GMP-related mechanisms. While stable, its in vivo half-life is short and its persistence is important for it to induce a response. Toxicities include an influenzia-like syndrome, anemia, eosinophilia, and fluid accumulation. In vivo actions include augmentation of cytotoxic responses at high doses, T-cell adjuvant actions, and T-cell restorative actions at midrange doses and at low doses with companion LKs. Antitumor responses in man and animals occur, but irregularly. They are maximized by the concomitant use of LAK cells, cytoreductive therapy, antisuppressor cell therapy, and regional or persistent administration. IL-2 offers hope for more effective therapy of cancer and a variety of immunodeficiency diseases involving IL-2 defects, including AIDS, viral infections, and autoimmune diseases.
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PMID:Recent advances in the preclinical and clinical immunopharmacology of interleukin-2: emphasis on IL-2 as an immunorestorative agent. 314 Oct 54

We have shown previously that stimulation of cloned murine T lymphocytes via the TCR inhibits their responsiveness to rIL-2. Signaling via the TCR is believed to result in a variety of biochemical events that include a rise in intracellular free calcium and activation (translocation) of protein kinase C. These two signals also can be generated by calcium ionophores, such as ionomycin, and by activators of protein kinase C, such as PMA. We report here that treatment of cloned murine T lymphocytes with PMA, ionomycin, or the combination led to a dose-dependent inhibition of IL-2-dependent proliferation but did not inhibit lymphokine secretion. Concentrations of PMA and ionomycin that maximally inhibited proliferation stimulated maximal lymphokine secretion and increased mitochondrial activity as assessed by measurement of cleavage of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium-bromide. Furthermore, PMA, ionomycin, the combination, or immobilized anti-CD3 mAb added after 12 to 16 h of culture with IL-2 could inhibit proliferation. These results demonstrate that PMA and ionomycin mimic stimulation of the TCR by high concentrations of immobilized anti-TCR mAb in that proliferation is inhibited and lymphokine secretion is induced. In addition, PMA or ionomycin could independently inhibit proliferation of some cells. These findings suggest that alternative mechanisms exist to regulate proliferation. Either increased levels of intracellular calcium or the physiologic events corresponding to those induced by PMA can inhibit IL-2-dependent replication of T lymphocytes.
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PMID:Agents that mimic antigen receptor signaling inhibit proliferation of cloned murine T lymphocytes induced by IL-2. 314

The role of macrophages in the regulation of inflammation and immunity is, in part, due to their secretory repertoire. Among the important mediators released by macrophages are the products of both the cyclooxygenase and lipoxygenase pathways of arachidonic acid (20:4) metabolism. The principal focus of this paper is the mechanism by which bacterial lipopolysaccharides (LPS) regulate 20:4 metabolism in macrophages. LPS has the capacity to prime macrophages for greatly enhanced 20:4 metabolism when the cells are subsequently challenged with a spectrum of triggers. Concomitant with priming, LPS also promotes the covalent attachment of myristic acid to a set of macrophage proteins. The time and concentration dependence of LPS-induced protein myristoylation is consistent with a role for myristoylation in LPS priming of the 20:4 cascade. One of the myristoylated proteins is a 68K (K = 10(3) Mr) protein kinase C substrate which associates with membranes upon myristoylation. LPS-primed macrophages show greatly increased phosphorylation of the 68K protein when the cells are subsequently treated with protein kinase C activating phorbol esters. It is proposed that the myristoylation of the 68K protein promotes its attachment to the membrane where it is more closely associated with activated protein kinase C (PKC), an association which would ensure more efficient catalysis during the mobilization and oxygenation of 20:4. This paper also examines protein myristoylation during T-cell-mediated activation of macrophages. Immune-activated macrophages have an enhanced capacity to kill several infectious agents by oxidative mechanisms. The lymphokine gamma-interferon (IFN gamma) rapidly induces the myristoylation of a 48K protein. This 48K protein is also myristoylated in murine macrophages that have been activated in vivo by intraperitoneal injection of Corynebacterium parvum, suggesting that it may be an important intermediate in the activation of macrophages for enhanced microbicidal capacity.
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PMID:Protein myristoylation as an intermediate step during signal transduction in macrophages: its role in arachidonic acid metabolism and in responses to interferon gamma. 315 94


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