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)

Thymocyte death is a complex phenomenon under the control of different signals and stimuli. We evaluated the effect of elevated temperature (heat shock, HS) on mouse thymocyte apoptosis. Incubation of thymocytes at 43 degrees C for 20 min induced DNA fragmentation and cell death, but it was also able to decrease the apoptosis induced by dexamethasone (DEX), TPA or Ca2+ ionophore. The anti-apoptotic effect was correlated with induction of heat shock proteins (HSPs) and abolished by protein synthesis inhibition. On the other hand, HS-induced unlike DEX-induced apoptosis was not inhibited by protein synthesis and mRNA transcription inhibitors, the PKC inhibitors H-7 and staurosporine, or interleukin-4 (IL-4), but only by Zn2+. These results suggest that HS interferes in thymocyte death by either inducing or inhibiting thymocyte apoptosis and that the induction process mechanisms are different from those of GCH.
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PMID:Heat shock induces apoptosis in mouse thymocytes and protects them from glucocorticoid-induced cell death. 151 81

Crosslinking of surface Ig receptors on mature B cells with mitogenic anti-Ig antibodies stimulates phosphoinositide breakdown with subsequent activation of protein kinase C (PKC) and elevation of [Ca2+]i leading to B-cell activation. This response can be mimicked using second messenger agonists such as phorbol 12,13-dibutyrate (PDB) plus a Ca2+ ionophore. Furthermore, interleukin-4 (IL-4) synergizes with sub-mitogenic concentrations of anti-Ig (or with PDB) to activate adult B cells. In contrast anti-Ig does not activate neonatal B cells but rather desensitizes or kills them. The nature of the signals involved in these effects on neonatal B cells is poorly understood. Here we have investigated the proliferative responses of small, resting B cells from 1-, 4-, 8-, and 12-week-old mice stimulated with combinations of anti-Ig, PDB, ionomycin and IL-4. We find that B cells from 8- and 12-week-old mice show an adult pattern of reactivity. B cells from 4-week-old mice respond to high doses of anti-Ig, anti-Ig + IL-4 and also to PDB + ionomycin + IL-4, but not to PDB + ionomycin alone. Neonatal (1-week-old) B cells respond only to the combination of PDB, ionomycin and IL-4. Most strikingly, pre-incubation of neonatal cells with anti-Ig completely abrogates this response, whilst IL-4 renders them refractory to such anti-Ig mediated inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of anti-immunoglobulin antibodies, interleukin-4 and second messenger agonists on B cells from neonatal mice. 183 47

Evidence is presented that human monocytes and acute myeloblastic leukemic (AML) cells contain both high and low affinity binding sites for interleukin-4 (IL-4). On monocytes 183 +/- 132 high affinity binding sites per cell with a Kd of 60 +/- 29 pM and 1500 +/- 600 low affinity receptors with a Kd of 2.3 +/- 0.4 nM (X +/- S.D., n = 6) could be demonstrated. On AML cells (n = 11) a comparable number and binding affinity of IL-4 receptors were observed (77 +/- 36 high affinity receptors with Kd 72 +/- 31 pM and 2400 +/- 1000 low affinity receptors with Kd of 2.2 +/- 0.7 nM). In addition, no cross-competition was shown between radiolabeled IL-4 and IL-1-alpha, IL-3, IL-6, IL-7, G-CSF, and GM-CSF. Both types of receptors on monocytes as well as on leukemic blasts could be down-modulated in a similar fashion by IL-4 and activators of protein kinase C (PKC), but not by the calcium ionophore A23187. The down-modulation by PKC activators was caused by an increased internalization, degradation and release of radiolabeled IL-4 in the medium. Finally, the functionality of the IL-4 receptors were tested on AML cells with a 3H-thymidine proliferation assay. In 8/11 cases IL-4 affected AML proliferation. These data demonstrate two different binding sites for IL-4 on normal and leukemic cells, which can be modulated by external activation signals in an analogous way.
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PMID:Expression and regulation of IL-4 receptors on human monocytes and acute myeloblastic leukemic cells. 194 30

By immunoblotting with antibodies for phosphotyrosine, we have demonstrated that the hematopoietic growth factors interleukin-2, interleukin-3, interleukin-4, and granulocyte-macrophage colony-stimulating factor stimulate the tyrosine phosphorylation of specific sets of proteins in murine hematopoietic progenitor cell lines. The stimulation of tyrosine phosphorylation is a receptor-dependent transient event. The effect of these hematopoietic growth factors on protein tyrosine phosphorylation was not mediated through protein kinase C.
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PMID:Hematopoietic growth factors activate the tyrosine phosphorylation of distinct sets of proteins in interleukin-3-dependent murine cell lines. 326 Mar 30

The murine macrophage cell line, J774, when activated with interferon-gamma (IFN-gamma), expressed high level of inducible nitric oxide synthase (iNOS) and bound significantly more [3H]-phorbol-dibutyrate (PBu2) compared to non-activated cells. The increased PBu2 binding to the particulate fraction of the cells is a measure of activation and translocation of protein kinase C (PKC). Both the expression of iNOS and the enhanced. PBU2 binding in the activated J774 cells were significantly inhibited by the pretreatment of the cells with murine recombinant interleukin-4 (IL-4). Stimulation of J774 cells by IFN-gamma and lipopolysaccharide results in the translocation predominantly of the epsilon isoform of PKC (PKC-epsilon), and this is inhibited by IL-4. The inhibition of PKC activation was also evident by measuring the PKC activity in the cytosolic-fraction of the IL-4-treated cells. Activated J774 cells pretreated with IL-4 or a PKC-specific inhibitor (RO31-8220) failed to express mRNA of iNOS analyzed by PCR. These results, therefore, suggest that the inhibition of nitric oxide synthesis in activated murine macrophages by IL-4 is at the transcriptional level and may involve the inhibition of the activation of PKC-epsilon.
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PMID:Inhibition of nitric oxide synthesis by interleukin-4 may involve inhibiting the activation of protein kinase C epsilon. 752 36

Both interleukin-4 (IL-4) and interleukin-13 (IL-13) induce the transcription factor NF-IL4 (nuclear factor IL-4) which preexists in an inactive form and binds to an IL-4 responsive element (IL-4RE) in the promoter regions of IL-4/IL-13-dependent genes. UV-crosslinking and SDS gel electrophoresis indicate that NF-IL4 consists of at least two DNA-binding components of 50 kDa and 100-130 kDa. The IL-4 responsive element is also recognized by an interferon-gamma (IFN-gamma)-induced DNA binding protein for which a Mr of 50 kDa has been determined. A common DNA binding motif for different transcription factors might provide the basis for the frequently observed functional antagonism between IL-4/IL-13 and IFN-gamma. The activation of transcription factors by IL-4/IL-13 and IFN-gamma could be blocked by inhibitors of tyrosine kinases and ser/thr phosphatases but not by a PKC inhibitor, suggesting related signal transduction pathways for these cytokines.
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PMID:Activation of gene transcription by IL-4, IL-13 and IFN-gamma through a shared DNA binding motif. 757 55

Reactive oxygen intermediates (e.g., superoxide [O2-]) generated by microglia may play a role in host defense and injury within the central nervous system. We investigated the effect of cytokines on human microglial cell O2- production on stimulation with phorbol myristate acetate. Priming of microglial cell cultures with interferon-gamma or tumor necrosis factor-alpha resulted in a dose- and time-dependent enhancement of O2- production. The priming effects of these cytokines were mediated through a protein kinase C signal transduction pathway. In contrast, astrocytes did not generate detectable O2- on phorbol myristate acetate stimulation. Treatment of microglia with transforming growth factor-beta, interleukin-4, or interleukin-10 suppressed in a dose-dependent manner the priming effects of tumor necrosis factor-alpha and interferon-gamma. The results of this study have implications for understanding the mechanisms by which cytokines and microglia contribute to processes of host defense and neurodegeneration via generation of reactive oxygen intermediates.
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PMID:Modulation of human microglial cell superoxide production by cytokines. 761 8

The CD20 molecule is a phosphoprotein expressed on the surface of B lymphocytes that plays a role in the regulation of B cell proliferation and differentiation. In this study it was found that monoclonal antibodies (mAb) directed to CD20 decrease the expression of IgM at the surface of normal human B lymphocytes and B cell lines. This effect was time-dependent with a half-time of about 5 h. Incubation of B cells with CD20 mAb B1 did not affect the steady-state level of IgM mRNA, suggesting that it acts at a nontranscriptional stage. Phorbol esters also produced inhibitory effect on surface IgM expression. Staurosporine reversed both the phorbol ester- and the CD20-induced down-regulation. Genistein did not reverse the down-regulation induced by the CD20 mAb B1. CD20 most likely triggers a protein kinase C-dependent pathway to down-regulate sIgM. CD20 mAb also counteracted the interleukin-4 (IL-4)-induced up-regulation of sIgM. The ability of anti-IgM to mobilize intracellular calcium was reduced in sIgM down-regulated cells, suggesting that B cells activation through the antigen receptor may be negatively regulated by CD20 and positively by IL-4.
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PMID:CD20 monoclonal antibodies down-regulate IgM at the surface of B cells. 768 Jun 16

In order to address a role of protein kinase C in signal transduction through interleukin-2, interleukin-4, and interleukin-9 receptors, we took advantage of the availability of a selective protein kinase C inhibitor, GF109203X, and the availability of TS1 beta and TS1 alpha beta cell lines which can be maintained in interleukin-2, interleukin-4, or interleukin-9 independently. In this report we report that inhibition of protein kinase C activity by GF109203X does not block interleukin-4- or interleukin-9-dependent proliferation and, on the contrary, does block interleukin-2-dependent proliferation, suggesting that interleukin-4 and interleukin-9 do not use signal transduction pathways mediated by protein kinase C and that the common gamma chain of interleukin-2, interleukin-4, and interleukin-9 receptors is not responsible per se for the activation of protein kinase C through interleukin-2 receptor. Moreover, GF109203X induces apoptosis in cells cultured in interleukin-2 but not in interleukin-4 or interleukin-9. Using antisense oligonucleotides, we report that the zeta and epsilon protein kinase C isoforms are involved in signaling through high-affinity interleukin-2 receptor and beta and zeta are involved in signaling through intermediate-affinity interleukin-2 receptor. Taken together, our data indicate that activation of the zeta, beta, and epsilon protein kinase C isoforms is an important step in interleukin-2-mediated proliferation.
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PMID:The zeta isoform of protein kinase C controls interleukin-2-mediated proliferation in a murine T cell line: evidence for an additional role of protein kinase C epsilon and beta. 773 51

Recombinant human interleukin-4 (rhIL-4) and rhIL-1 alpha each produced a rapid down-modulation of tumour necrosis factor receptor (TNFR) on rheumatoid synovial fibroblasts (RSF) in vitro. This was associated with a staurosporine-resistant increase in p55 soluble TNFR levels, in culture media, suggesting that down-modulation was due to enhanced receptor shedding via a protein kinase C-independent mechanism. Pretreatment with rhIL-4 reduced the subsequent tumour necrosis factor alpha (TNF alpha) stimulation of prostaglandin E (PGE) and matrix metalloproteinase-3 (MMP-3) production by RSF. Thus, the potential anti-synovial monokine properties of rhIL-4 are not confined to inhibiting monokine production but also include the ability to interfere with their action on cells that constitute a substantial proportion of the rheumatoid synovium.
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PMID:Interleukin-4 (IL-4) induces down-modulation and shedding of the p55 tumour necrosis factor receptor and inhibits TNF alpha's effect on rheumatoid synovial fibroblasts. 793 36


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