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)

Interferon-gamma (IFN-gamma) is an important immunoregulatory protein produced predominantly by T cells and large granular lymphocytes (LGL) in response to different extracellular signals. In particular, two interleukins (ILs), IL-2 and IL-12, have been shown to be potent inducers of IFN-gamma gene expression in both T cells and LGL. Although it has been reported that there are some T cell lines that produce IFN-gamma in response to IL-2 and IL-12 stimulation, there has as yet been no report of a natural killer (NK) cell line that responds in a similar manner. In this report we present evidence that the cell line NK3.3 derived from human NK cells, responds to both IL-2 and IL-12, as measured by increases in IFN-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF) cytoplasmic mRNA and protein expression. In addition, when used together IL-2 and IL-12 synergized in the induction of IFN-gamma and GM-CSF and this synergy was attributed to an increased accumulation and stability of the IFN-gamma and GM-CSF mRNAs. To investigate the signaling pathways involved in the gene induction, five inhibitors, cyclosporin A (CsA), transforming growth factor-beta, cycloheximide, genistein, and staurosporine A, were used in analyzing the effects of IL-2 and IL-12 on NK3.3 cells. The results suggest that activation of protein kinase C, but not new protein synthesis, is required for IL-2 induction of IFN-gamma and GM-CSF cytoplasmic mRNA. In contrast, IL-12 induction of IFN-gamma cytoplasmic mRNA appears to only partially depend on activation of protein kinase C. Furthermore, both transforming growth factor-beta and genistein, a tyrosine kinase inhibitor, could suppress IL-2 and IL-12 signaling but CsA was generally inactive. It also was observed that suppression of cytokine gene expression by these agents was independent of the inhibition of proliferation. In addition, IL-2 but not IL-12 induced nuclear factors NF-kappa B and AP1, and regulation of the nuclear levels of these two DNA binding protein complexes is correlated with IFN-gamma and GM-CSF gene expression. These data indicate that IL-2 and IL-12 may have distinct signaling pathways leading to the induction of IFN-gamma and GM-CSF gene expression, and that the NK3.3 cell line may serve as a novel model for dissecting the biochemical and molecular events involved in these pathways.
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PMID:Cellular and molecular mechanisms of IFN-gamma production induced by IL-2 and IL-12 in a human NK cell line. 764 15

IL-4 synergizes with signals delivered through CD40 both for the induction of CD23/Fc epsilon RII expression and for IgE synthesis. Moreover, engagement of CD40 on the B cell surface by MoAb overcomes the ability of interferons, transforming growth factor-beta, or anti-CD19 to inhibit IL-4-dependent change. We now report that occupancy of CD40 relieves potent suppression of IL-4-induced CD23 production by glucocorticoid or the relatively broad-acting kinase inhibitor staurosporine. Interruption of the IL-4 signal was observed with concentrations of staurosporine considered to be selective for protein kinase C (PKC) inhibition (IC50 = 10 nM) but not with genistein or tyrphostins, effective inhibitors of tyrosine kinase activity. On ligation of CD40, staurosporine no longer inhibited the IL-4 signal: at concentrations of between 1 and 20 nM, staurosporine actually increased by as much as 100% the rate of CD23 production stimulated on simultaneous activation through CD40 and IL-4R. Such augmentation was not observed when the more specific PKC inhibitor RO-31-8220 was used; indeed, CD40 engagement was unable to overcome the ability of this inhibitor to block IL-4-promoted CD23 induction (IC50 = 10 microM). Occupancy of CD40 did, however, thwart completely the usual ability of prednisolone to inhibit the IL-4 signal leading to CD23 induction. Activation through CD40 left inhibition of phorbol ester-induced CD23 expression by staurosporine, RO-31-8220, or glucocorticoid unchecked. These findings further highlight the intimate level of cross-talk existing between CD40 and IL-4R on resting B lymphocytes to promote CD23 expression, a phenotypic change which preludes IgE synthesis.
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PMID:Inhibition by glucocorticoid and staurosporine of IL-4-dependent CD23 production in B lymphocytes is reversed on engaging CD40. 768 90

Accumulation of oxidized low density lipoproteins in macrophages and smooth muscle cells causes foam cell formation, an initial step in atherosclerosis. Active oxygen species are considered important in the pathogenesis of the disease. Antioxidants, such as tocopherols and tocotrienols have been considered to prevent the deleterious effects of active oxygen species. We found native low density lipoproteins can stimulate directly smooth muscle cell proliferation, it is associated with an increase of protein kinase C activity. d-alpha-Tocopherol, biologically most active form of vitamin E, inhibits both cell proliferation and protein kinase C activity. The effect of d-alpha-tocopherol is not related to its radical scavenging properties. Transforming growth factor-beta secreted by smooth muscle cells as growth inhibitor. Low density lipoproteins decrease the release of transforming growth factor-beta from smooth muscle cells thus activating growth. d-alpha-Tocopherol activates the cellular release of transforming growth factor-beta. These new aspects explain the important role of low density lipoproteins and vitamin E in increasing and decreasing the risk of atherosclerosis, respectively.
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PMID:New roles of low density lipoproteins and vitamin E in the pathogenesis of atherosclerosis. 773 26

High concentrations of glucose in vitro inhibit cell proliferation and stimulate matrix protein synthesis. These studies sought to characterize the relationship between the effects of glucose on cell proliferation and matrix synthesis and to assess the mechanism(s) responsible for these cellular effects of glucose. The initial experiments showed that high glucose levels stimulate fibronectin (FN) synthesis by human mesangial cells (HMC) but only in those cultures in which cell proliferation was inhibited by glucose. To assess whether this relationship was due to an effect of glucose on the capacity of HMC to respond to cytokines, the responses of HMC to serum or cytokines were measured in the presence of different glucose concentrations. High concentrations of glucose inhibited (3H)thymidine incorporation in response to serum and platelet-derived growth factor. Under the conditions of these experiments, transforming growth factor-beta (TGF-beta) also stimulated thymidine incorporation by HMC, and high glucose concentrations inhibited thymidine incorporation in response to TGF-beta. In contrast, high concentrations of glucose did not inhibit the stimulation of FN synthesis caused by platelet-derived growth factor, serum, or TGF-beta. The antiproliferative effects of high glucose levels were first observed after 48 h of incubation and were reversible after the withdrawal of high glucose from the media. The following evidence suggest that the effects of glucose may be mediated via protein kinase C (PKC): (1) incubation with high glucose concentrations caused an increase in HMC PKC levels; (2) PKC activation with phorbol esters inhibited HMC proliferation; and (3) depletion or inhibition of PKC stimulated HMC proliferation and prevented the antiproliferative effects of glucose. In contrast to these findings, inhibitors of protein glycosylation and myo-inositol supplementation of culture media did not prevent the antiproliferative effects of glucose. In conclusion, high glucose concentrations acutely and reversibly inhibit HMC proliferation, perhaps by a PKC-dependent mechanism. Because PKC can also stimulate FN synthesis, glucose-induced changes in PKC may explain the relationship between the effects of high glucose concentrations on cell proliferation and FN synthesis.
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PMID:Effects of high glucose concentrations on human mesangial cell proliferation. 775 94

Low-density lipoprotein (LDL) cholesterol has been implicated in the pathogenesis of glomerulosclerosis in diabetes and other forms of glomerular injury. In the present study we evaluated the effect of LDL on fibronectin synthesis in cultured rat mesangial cells (MCs) and the roles of protein kinase C (PKC) and transforming growth factor-beta (TGF-beta) in mediating this LDL action. In MCs, 25 micrograms to 100 micrograms/ml LDL increased PKC activity within 15 minutes, as reflected by enhanced in situ phosphorylation of the 80 kd myristoylated alanine-rich C kinase substrate protein, a specific endogenous substrate of PKC in MC. The same concentrations of LDL subsequently (18 to 72 hours) enhanced fibronectin synthesis, as reflected by increased incorporation of labeled methionine into fibronectin. GF 109203X, a selective inhibitor of PKC, blocked increases in both PKC activity and fibronectin synthesis induced by LDL in MCs. Furthermore, prior downregulation of PKC to less than 1% of basal activity by exposure of MCs to 0.5 mumol/L phorbol myristate acetate (PMA) also prevented LDL stimulation of fibronectin synthesis. The activation of PKC by LDL seen after 15 minutes of exposure was transient and was not observed after 4 or 48 hours of exposure of MCs to LDL. However, exposure to LDL for 48 hours, but not for 15 minutes or 4 hours, increased both maximal PKC responses to phorbol dibutyrate (PDBu) and tritiated PDBu binding to MCs by 30%. These findings suggest that chronic exposure to LDL increases the total PKC content in MCs and thereby might modulate responses to other PKC agonists. Neither the cyclooxygenase inhibitor piroxicam nor the thromboxane/prostaglandin endoperoxide receptor blocker Sq-29548 altered LDL stimulation of fibronectin synthesis in MCs, suggesting that this action of LDL was not mediated by changes in MC eicosanoid generation. By contrast, antibody to TGF-beta blocked LDL stimulation of fibronectin synthesis in MCs. TGF-beta bioactivity, determined with the mink lung epithelial cell assay, was two to three times higher in the medium of MCs cultured with LDL for 24 to 48 hours as compared with corresponding control values. Total TGF-beta bioactivity examined after heat activation of latent TGF-beta was also two times higher in the medium of MCs exposed to LDL as compared with that of controls. Prior down-regulation of PKC by exposure of MCs to PMA blocked the increases in TGF-beta bioactivity induced by LDL.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Low-density lipoprotein stimulation of mesangial cell fibronectin synthesis: role of protein kinase C and transforming growth factor-beta. 782 50

Vitamin D metabolites appear to regulate chondrocytes and osteoblasts via a combination of genomic and nongenomic mechanisms. Specificity of the nongenomic response to either 1,25-(OH)2D3 or 24,25-(OH)2D3 may be conferred by the chemical composition of the target membrane and its fluid mosaic structure, by the presence of specific membrane receptors, or by the interaction with classic vitamin D receptors. Nongenomic effects have been shown to include changes in membrane fluidity, fatty acid acylation and reacylation, arachidonic acid metabolism and prostaglandin production, calcium ion flux, and protein kinase C activity. Chondrocytes metabolize 25-(OH)D3 to 1,25-(OH)2D3 and 24,25-(OH)2D3; production of these metabolites is regulated by both growth factors and hormones and is dependent on the state of cell maturation. 1,25-(OH)2D3 and 24,25-(OH)2D3 may interact directly with extracellular matrix vesicles to regulate their function in the matrix, including protease activity, resulting in matrix modification and calcification. Isolated matrix vesicles, produced by growth zone chondrocytes, can activate latent transforming growth factor-beta when incubated with exogenous 1,25-(OH)2D3. These observations suggest that nongenomic regulation of matrix vesicle structure and function may be a mechanism by which mesenchymal cells, like osteoblasts and chondrocytes, may modulate events in the extracellular matrix at sites distant from the cell surface.
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PMID:Nongenomic regulation of extracellular matrix events by vitamin D metabolites. 787 26

We investigated the role of protein kinase C (PKC) in osteoblast function using a set of putative PKC modulating factors and an in situ peptide substrate-based kinase assay in different types of osteoblastic cells. Primary calvarial rat osteoblastic cells (ROB) and ROS 17/2.8 osteosarcoma cells showed an equally high PKC activity when a maximal dose of PKC-activating phorbol ester was applied. The osteosarcoma cell line UMR 106-01 showed only 5-10% of this maximal PKC activity. All 3 cell types responded to 10 U/ml thrombin with a 2-fold stimulation of PKC activity. However, no distinct direct effects of parathyroid hormone (bPTH (1-34)) or transforming growth factor-beta 2 (TGF-beta 2) were found in either of the cell types. The thrombin-induced stimulation of PKC was associated with an increase in the PTH-mediated cAMP response of ROB. Down-regulation of PKC-activity was found when ROB were treated for 24 h with phorbol ester and, interestingly, also after a 24 h treatment with bPTH (1-34) and TGF-beta 2. We conclude that differences in PKC activity exist among osteoblastic cell types, which may be related to their different proliferative activity. Direct PKC activation may lead to modulation of the cAMP signaling pathway. Down-regulation of PKC activity by bPTH (1-34) and TGF-beta 2 provides an interesting possible mechanism for the long-term regulation of signal transduction.
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PMID:Regulation of protein kinase C activity by phorbol ester, thrombin, parathyroid hormone and transforming growth factor-beta 2 in different types of osteoblastic cells. 799 86

Studies were undertaken to characterize the cytokines and cytokine-cytokine interactions that stimulate human lung fibroblast leukemia inhibitory factor (LIF) production and the mechanisms of these regulatory effects were investigated. Unstimulated fibroblasts did not produce significant amounts of LIF, whereas recombinant interleukin-1 alpha (rIL-1 alpha), transforming growth factor-beta (TGF-beta), and recombinant tumor necrosis factor (rTNF) were dose-dependent stimulators of LIF production. TGF-beta and rIL-1 alpha also interacted in a synergistic fashion to further increase LIF elaboration. Under all conditions alterations in LIF production were associated with comparable alterations in LIF mRNA accumulation. The kinetics of mRNA induction, however, differed with rIL-1-induced LIF mRNA being readily detected after 2 h, TGF-beta 1 induction peaking after 16-24 h, and the induction caused by rIL-1 alpha plus TGF-beta 1 being most prominent after 2-4 h and decreasing with additional incubation. Protein synthesis was not required for LIF induction. In addition, even though A23187 was an effective stimulator of LIF production, the calmodulin antagonists W-7 and trifluoperazone dichoride (TFP) did not significantly alter the LIF-stimulatory effects of IL-1 and TGF-beta. PKC did appear to play an important role in this induction, however, since LIF was induced by PMA and cytokine induction of LIF production was markedly diminished by chronic phorbol ester preincubation, staurosporine, and H-7, but not by HA1004. These studies demonstrate that 1) rIL-1, TGF-beta, TNF, agents that increase intracellular calcium and agents that activate PKC, stimulate lung fibroblast LIF production; 2) rIL-1 and TGF-beta interact in a synergistic fashion to further increase fibroblast LIF production; and 3) rIL-1 and TGF-beta stimulate lung fibroblast LIF production via a pretranslational activation pathway that is largely PKC-dependent and protein synthesis-, cyclic nucleotide-, and calmodulin-independent. Cytokine-stimulated LIF production may play an important role in homeostasis and repair in the human lung.
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PMID:Cytokine-cytokine synergy and protein kinase C in the regulation of lung fibroblast leukemia inhibitory factor. 817 19

The importance of receptor expression and protein kinase C to epidermal growth factor (EGF)-induced cell proliferation was studied in LLC-PK1 kidney cells. These cells have both high- and low-affinity binding sites for EGF. Neither transforming growth factor-beta nor tumor necrosis factor altered EGF receptor expression. On the other hand, retinoic acid induced a concentration-dependent increase in EGF binding that was maximal at 1 mumol/L. One micromolar of retinoic acid increased EGF binding from 0.38 +/- 0.01 fmol/10(6) cells in controls to 1.10 +/- 0.03 fmol/10(6) in treated cells at 18 hours (n = 8, P < 0.001). The increase in binding was the result of an increase in the Bmax of the high-affinity receptor. The upregulation of the EGF receptor induced by retinoic acid was associated with enhanced EGF-induced growth promotion. A 45-minute incubation of cells with phorbol 12-myristate 13-acetate caused a concentration-dependent decrease in EGF binding that was prevented by a 40-hour, 2 mumol/L pre-exposure to phorbol 12-myristate 13-acetate; 10(-8) mol/L EGF also caused a downregulation of the EGF receptor that was not prevented by phorbol 12-myristate 13-acetate or retinoic acid. Downregulation of protein kinase C did not interfere in the capacity of EGF to induce growth in these cells. These studies demonstrate that EGF receptor upregulation plays an important role in the control of EGF-induced cell growth. Protein kinase C regulates EGF binding in these cells; however, it is not necessary for EGF-induced growth promotion or receptor downregulation.
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PMID:Regulation of epidermal growth factor receptor expression and growth by protein kinase C and retinoic acid in LLC-PK1 cells. 825 33

We studied the regulation of endothelin (ET)-1 gene expression in porcine thyroid cells in culture. First, we demonstrated prepro-ET-1 mRNA in porcine thyroid cells. The level of the mRNA was increased by phorbol 12-myristate 13-acetate (TPA), a protein kinase C stimulator, but was decreased by TSH (1 mU/mL). However, transforming growth factor-beta and interleukin-1 beta had no effect. The amount of immunoreactive (ir)-ET-1 secreted from the cells was also increased by TPA and was decreased by TSH. Next, we studied the effect of iodide, as iodide has various effects on thyroid cells. NaI (100 microM) increased the prepro-ET-1 mRNA level. The effect of NaI was attenuated by 1 mM methimazole (MMl). The amount of ir-ET-1 released from the cells was also increased by the NaI treatment and the increase was also attenuated by MMl. These observations indicate that ET-1 gene expression is induced by organified iodine compounds in thyroid cells in a manner very similar to the inhibitory actions of iodide on thyroid cell function. The protein synthesis inhibitor, cycloheximide, superinduced prepro-ET-1 mRNA within 4 h, but NaI did not. The difference between cycloheximide and NaI suggests that the iodine effect on the gene expression is not due to nonspecific inhibition of protein synthesis. Together with our previous findings that porcine thyroid cells have ET-1 receptors and that ET-1 modulates iodine metabolism, we speculate that ET-1 produced by thyroid cells is involved in thyroid autoregulation including thyroid blood flow.
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PMID:Iodine regulation of endothelin-1 gene expression in cultured porcine thyroid cells: possible involvement in autoregulation of the thyroid. 825 66


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