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)

Proteoglycan biosynthesis was studied in human monocytes and monocyte-derived macrophages (MDM) after exposure to typical activators of the monocyte/macrophage system: interferon-gamma (IFN-gamma), lipopolysaccharide (LPS), and phorbol 12-myristate 13-acetate (PMA). By morphological examination, both monocytes and MDM were stimulated by these activators. Treatment with IFN-gamma resulted in a slight decrease in the expression of [35S]chondroitin sulfate proteoglycan (CSPG) in both monocytes and MDM, whereas LPS treatment increased the [35S]CSPG expression 1.8 and 2.2 times, respectively. PMA, in contrast, decreased the CSPG expression 0.4 times in monocytes, whereas MDM were stimulated to increase the biosynthesis 1.9 times. An increase in the sulfate density of the chondroitin sulfate chains was evident following differentiation of monocytes into MDM due to the expression of disulfated disaccharide units of the chondroitin sulfate E type (CS-E). However, monocytes exposed to PMA did also express disaccharides of the chondroitin sulfate E type. Furthermore, the expression of CS-E in MDM was increased 2 times following PMA treatment. An inactive phorbol ester, phorbol 12,13-diacetate, did not affect the expression of CS-E in either monocytes or MDM when compared with control cultures, suggesting that protein kinase C-dependent signal pathways may be involved in the regulation of sulfation of CSPG. Exposure to LPS or IFN-gamma did not lead to any changes in the sulfation of the chondroitin sulfate chains.
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PMID:Modulation of the expression of chondroitin sulfate proteoglycan in stimulated human monocytes. 276 47

Human monocytes purified by elutriation were cultured for 3 d in Teflon bags with or without human recombinant interferon-gamma (rIFN gamma). The cells were then collected and used in suspension to determine the rate of stimulus-dependent superoxide or hydrogen peroxide formation as a measure of the NADPH-oxidase. The treatment with IFN gamma increased this rate two- to threefold when phorbol myristate acetate (PMA) was used as the stimulus. By contrast, no IFN gamma-dependent increase in superoxide production was observed when the cells were stimulated with different concentrations of the receptor agonist N-formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe) alone or in combination with another receptor agonist, platelet-activating factor (PAF). At optimum concentrations, f-Met-Leu-Phe elicited rates of superoxide formation that could not be exceeded under other stimulatory conditions including PMA after treatment with IFN gamma. It thus appears that f-Met-Leu-Phe can lead to maximum activation of the NADPH-oxidase, and that this response is not influenced by IFN gamma. Treatment with IFN gamma also failed to affect the affinity of PMA- or f-Met-Leu-Phe-stimulated oxidase for NADPH, the Km values being 30 to 40 microM under all conditions. IFN gamma did not alter the cellular levels of cytochrome b558, as measured by low-temperature spectroscopy, and protein kinase C, as measured by [3H]phorbol dibutyrate binding, and did not appreciably influence the stimulus-dependent increase of cytosolic free calcium. These results indicate that activation of human mononuclear phagocytes by IFN gamma does not affect the level and the kinetic properties of NADPH-oxidase or its activation by receptor agonists. They confirm, however, that IFN gamma enhances the respiratory burst response to PMA.
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PMID:Activation of monocytes by interferon-gamma has no effect on the level or affinity of the nicotinamide adenine dinucleotide-phosphate oxidase and on agonist-dependent superoxide formation. 283 24

Treatment of mouse EL-4 cells with intracellular activators of protein kinase C, namely 4-phorbol 12-myristate 13-acetate (PMA) and diacylglycerol, resulted in 90% reduction in cell surface interferon-gamma (IFN-gamma) receptors as judged by iodinated-IFN-gamma binding. This did not seem to be due to a decreased in the receptor affinity, since that of the remaining surface receptors appeared to be significantly increased as shown in Scatchard plot analysis. Kinetics experiments revealed that a PMA treatment as short as 15 min was sufficient to induce a decrease of 30% of IFN-gamma receptors, whereas the highest levels of down-regulation were observed after 60-90 min. Treatment of EL-4 cells with calcium ionophore, A23187, although ineffective by itself, dramatically increased the ability of suboptimal PMA concentrations to mediate IFN-gamma receptor down-regulation. Finally, specificity studies revealed that PMA is particularly effective in decreasing the binding of IFN-gamma to T-lymphocytes. Altogether these results suggest a possible involvement of protein kinase C in the regulation of IFN-gamma receptor expression.
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PMID:Activation of protein kinase C down-regulates IFN-gamma receptors. 295 37

Preincubation of macrophages with immune complexes suppresses the interferon-gamma (IFN-gamma) induction of tumouricidal activity and Ia surface expression. The studies reported in this manuscript were designed to test if immune complexes alter the interaction of IFN-gamma with macrophages. The binding of IFN-gamma to its specific cellular receptor, the uptake or the degradation were not affected by preincubation of macrophages with immune complexes. Preincubation of macrophages with high doses of phorbol esters mimics the inhibitory effect of immune complexes. This suggests that a strong activation of protein kinase C suppresses a subsequent activation of macrophages by IFN-gamma.
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PMID:Immune-complex inhibition of macrophage activation is not due to an interaction with the binding or processing of IFN-gamma. 296 50

The adenylate cyclase activator, forskolin, was found to induce expression of class I and class II major histocompatibility complex antigens in a B precursor cell line, Reh, as well as in a B lymphoid cell line, Raji. No such effect was, however, observed when the promyelocytic cells line HL-60 was treated with either forskolin or the cAMP analogue 8-bromoadenosine cyclic monophosphate. As expected, all three cell lines showed reduced proliferation upon forskolin treatment. Forskolin induced expression of class I and class II major histocompatibility complex antigens in cell lines not affected by interferon-gamma and vice versa, indicating that cAMP is not involved in the regulation of histocompatibility antigens by interferon-gamma. We also compared the effect of interferon-gamma and 12-O-tetradecanoylphorbol 13-acetate on major histocompatibility complex class I and class II expression, and despite differences in the response on the tested cell lines, we can not at this point exclude the possibility that protein kinase C is involved in the action of interferon-gamma.
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PMID:Distinct effect of forskolin and interferon-gamma on cell proliferation and regulation of histocompatibility antigen expression in hematopoietic cells. 308 31

These studies were designed to test the hypothesis that changes in intracellular Ca2+ levels and activation of the calcium ion- and phospholipid-dependent protein kinase C were required for the induction of macrophage tumoricidal activity by interferon-gamma (IFN-gamma). Phenothiazines and R24571, known antagonists of calcium-binding proteins and therefore nonspecific inhibitors of protein kinase C, blocked in a dose-dependent manner the induction of macrophage cytocidal activity by either natural or recombinant IFN-gamma. Macrophages depleted of intracellular Ca2+ by chelation with Quin 2, were also unresponsive to IFN-gamma. These treatments effected neither the binding of IFN-gamma to its cell surface receptor nor the normal intracellular processing of IFN-gamma. Activators of protein kinase C (such as phorbol esters) and Ca2+ ionophores when added alone did not effect the activation state of the macrophage population. However, macrophages exposed to both drugs in combination were elevated into the primed activation state such that in the presence of a second signal (lipopolysaccharide or heat killed Listeria monocytogenes), the cells were triggered to express full levels of tumoricidal activity. The capacity of phorbol esters to induce cellular activation correlated with their ability to bind and to activate protein kinase C. No synergistic effect was observed between IFN-gamma and protein kinase C activators and/or Ca2+ ionophores, indicating that the drugs could only prime and could not trigger macrophages for tumor cell killing. These results thus support the concept that protein kinase C activation and mobilization of intracellular Ca2+ are essential steps in the pathway of IFN-gamma-dependent induction of non-specific tumoricidal activity in macrophages.
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PMID:Role of protein kinase C and intracellular calcium mobilization in the induction of macrophage tumoricidal activity by interferon-gamma. 309 74

Interleukin 2 (IL 2) induces specific mRNA synthesis and secretion of an important immunoregulatory molecule, interferon-gamma (IFN-gamma). We have observed that treatment of an IL 2 independent murine T cell line, BUD-27, with IL 2, calcium ionophore A23187, or agents that activate phospholipid/Ca2+-dependent protein kinase C results in increased IFN-gamma mRNA transcription and release of anti-viral activity. These same agents each induced the subcellular redistribution of protein kinase C from cytosol to plasma membrane in both the BUD-27 cell line and its IL 2-dependent parent, CT6. Ionophore concentrations greater than 1 micron exhibited the most significant induction of IFN-gamma mRNA, which also correlated with the dose of ionophore, inducing translocation of protein kinase C. This correlation between increased mRNA levels and protein kinase C translocation suggests that a calcium-dependent event is involved in induction of IFN-gamma mRNA synthesis. Furthermore, the magnitude of the translocation of protein kinase C from cytosol to plasma membrane corresponded to the physiologic IL 2 dose-response for IFN-gamma secretion. The data suggest that the activation of protein kinase C and/or coordinate elevation of intracellular calcium may provide at least one mechanism of signal transduction for the regulation of IFN-gamma gene transcription.
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PMID:Interleukin 2 induction of interferon-gamma mRNA synthesis. 309 33

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

The murine Ly-6A.2 and Ly-6E.1 antigens, which can transduce triggering signals in T cells, have been shown to become highly expressed after mitogenic stimulation. It has recently been found that enhanced expression of Ly-6A/E antigens is also induced by interferon-gamma (IFN-gamma) in resting T cells. Here, the possibility is investigated that Ly-6A/E induction on activated T cells may be due to the IFN-gamma known to be secreted by these cells. A potent neutralizing anti-IFN-gamma monoclonal antibody (mAb) (H-22.10) was used. This mAb was found to abrogate the augmentation of Ly-6A/E antigens produced in resting T cells by supernatants from T cells stimulated with concanavalin A. When added directly into cultures of T cells stimulated with concanavalin A or by the combination of ionomycin with the protein kinase C activator phorbol myristate acetate (PMA), the H-22.10 mAb inhibited Ly-6A/E enhancement without affecting the blastogenesis or the emergence of interleukin 2 receptors and transferrin receptors. Such a selective effect of the anti-IFN-gamma mAb indicated that IFN-gamma is involved in the up-regulation of Ly-6A/E antigens during T cell activation. In determining whether other activation signals, in addition to IFN-gamma receptor occupancy, may contribute to Ly-6A/E enhancement, it was found that suboptimal stimulation of BALB/c T cells provided by a 3-hr pulse with ionomycin plus PMA or by culture with PMA alone potentiated by about twofold the increase of Ly-6E.1 induced by exogenous IFN-gamma. Therefore, Ly-6A/E augmentation in activated T cells reflects primarily an action of endogenous IFN-gamma that is amplified (in BALB/c mice) by a protein kinase C-dependent step.
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PMID:The augmentation of surface Ly-6A/E molecules in activated T cells is mediated by endogenous interferon-gamma. 312 27

The macrocyclic lactone bryostatins, isolated from marine bryozoans, have been found to be strong inhibitors of e.g., the P 388 murine lymphocyte leukemia cell line and in vivo systems. Presently, bryostatin 1 is under preclinical development as a potential anticancer drug, although the bryostatins exhibit some of the same biological effects as the tumor promoting phorbol-12-myristate-13-acetate (PMA), especially activation of protein kinase C in certain cell types. In our experiments, we investigated the influence of bryostatin 1 on the synthesis of interleukin 2 (IL2) and interferon-gamma (IFN-gamma) by ionophore A23187 or mitogen-induced human blood lymphocytes. These results were then compared with those achieved using the two tumor promotors PMA and teleocidin. Our data indicate that bryostatin 1 is comparable to these two other drugs in increasing production of the two lymphokines 10-100-fold. The IL2 and IFN-gamma production kinetics of cultures induced with either A23187/bryostatin 1 or A23187/PMA were practically identical. The general pattern of peptides, however, released from bryostatin 1 coinduced cultures differed from that obtained when PMA was used.
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PMID:Co-induction of lymphokine synthesis by the antineoplastic bryostatins. 312 67


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