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)

Phagocytosis of Giardia lamblia trophozoites by cytokine-activated and non-activated bone marrow-derived macrophages was examined in vitro. Macrophages treated with recombinant interferon-gamma (IFN-gamma) and bacterial lipopolysaccharide (LPS) ingested a significantly higher number of in vitro-grown trophozoites than untreated macrophages. Maximal uptake of parasites occurred after 4 h and 6 h of incubation where 81.4% and 79.1% of macrophages were positive for trophozoites. Other cytokines tested, IL-2, IL-3, IL-4, IL-5, GM-CSF, CSF-1 and tumour necrosis factor-alpha (TNF-alpha) either alone or in combination with LPS, failed to activate macrophages to phagocytose G. lamblia. The induction of this activated macrophage anti-microbial function was achieved pharmacologically using phorbol myristate acetate (PMA) and ionophore A23187. The giardicidal activity of macrophages activated with IFN-gamma and LPS or that induced by PMA and A23187 was inhibited by H-7, indicating the role for protein kinase C in the intracellular events following activation.
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PMID:Phagocytosis of Giardia lamblia trophozoites by cytokine-activated macrophages. 173 94

Proliferative and interleukin responses to T-cell mitogens such as concanavalin A (Con A) were rapidly and progressively reduced in BALB/c mice infected with the Friend leukemia complex (FLC) or its helper, Friend murine leukemia virus (F-MuLV). In contrast, a combination of the protein kinase C activator phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) and the Ca++ ionophore A23187 elicited a normal lymphoproliferative response up to 8 days postinfection (p.i.) and normal interleukin-2 (IL-2) and interferon-gamma responses up to day 14 p.i. Exogenous IL-2 failed to restore the lymphoproliferative response of infected cells regardless of the stimulation used. These results showed that the T-cell deficits may be at least partly attributable to a derangement of the signal transduction pathway leading to activation. Spleen cells passed through nylon wool columns reacquired a normal responsiveness to Con A +/- TPA up to 14 days p.i. The latter finding suggests that the alterations in signal transduction are not caused by primary defect of the responder-T cells but may result from an extrinsic suppressive mechanism.
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PMID:Alterations of T-cell functions during Friend leukemia complex infection: defective signal transduction? 181 Mar 22

We investigated the effects of interferon-gamma (IFN-gamma), phorbol myristate acetate (PMA), and dibutyryl cAMP (Bt2cAMP) on Fc gamma R subtype expression on a human eosinophilic leukemia cell line, EoL-3. Unstimulated EoL-3 cells expressed Fc gamma RII as determined by monoclonal antibody (mAb) IV-3, whereas there was little or no Fc gamma RI and Fc gamma RIII expression as determined by mAbs 32.2 and 3G8, respectively. IFN-gamma induced Fc gamma RI expression, and Bt2 cAMP, which did not induce Fc gamma RI expression by itself, showed an additive effect on IFN-gamma-induced Fc gamma RI expression. Fc gamma RII expression was augmented by IFN-gamma, PMA, and Bt2 cAMP. Bt2 cAMP also showed an additive effect on IFN-gamma-augmented Fc gamma RII expression. Fc gamma RIII expression could be induced only by IFN-gamma plus Bt2 cAMP. H-7, a protein kinase C (PK-C) inhibitor, suppressed the enhancement of Fc gamma R subtype expression induced by these reagents. These results show that Fc gamma R subtype expression on EoL-3 cells is regulated differently in each subtype and that cAMP and PK-C play important roles in the regulation.
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PMID:Regulation of Fc gamma receptor subtype expression on a human eosinophilic leukemia cell line EoL-3: participation of cAMP and protein kinase C in the effects of interferon-gamma and phorbol ester. 184 82

Tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma) are immune-modulating cytokines that exert synergistic cytotoxic effects in several types of tumor cells, including ASPC-1 human pancreatic carcinoma cells. Lymphotoxin (LT), is a cytokine that binds to the TNF receptor and mimicks most of the biological actions of TNF. In the present study, we examined ASPC-1 cells for cytokine-mediated modulation of TNF and IFN-gamma receptors. Treatment of ASPC-1 cells with recombinant human IFN-gamma (rhIFN-gamma) did not significantly alter 125I-rhTNF binding. In contrast, treatment with rhTNF led to a dose- and time-dependent increase in 125I-rhIFN-gamma binding and internalization. Scatchard analysis revealed that rhTNF increased the number of 125I-rhIFN-gamma binding sites from 11,000 sites/cell to 23,000 sites/cell without altering receptor affinity. Although rhLT also increased 125I-rhIFN-gamma binding, it was 100-fold less potent than rhTNF. In contrast, rhLT was only 10-fold less potent than rhTNF in displacing 125I-rhTNF from its receptor. The phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) blocked the rhLT- and rhTNF-mediated increase in 125I-rhIFN-gamma binding and markedly decreased 125I-rhTNF binding. These data suggest that both TNF and LT upregulate IFN-gamma receptors in ASPC-1 cells, but that LT is much less efficient than TNF. Further, the TPA-induced attenuation of IFN-gamma receptor upregulation suggests that protein kinase C activation can regulate the TNF/LT-mediated pathways involved in IFN-gamma receptor upregulation.
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PMID:Upregulation of interferon-gamma binding by tumor necrosis factor and lymphotoxin: disparate potencies of the cytokines and modulation of their effects by phorbol ester. 190 42

The general way to induce the synthesis of lymphokines by T cells is the stimulation through the T cell receptor (TcR) complex which results in an increase of intracellular [Ca2+] and in the activation of a tyrosine kinase as well as of protein kinase C. Lymphokine production induced via the TcR is inhibited by the immunosuppressive drug cyclosporin A (CsA). However, an alternative pathway of lymphokine production exists. Several T lymphocyte clones can synthesize interferon-gamma (IFN-gamma), granulocyte-monocyte colony-stimulating factor, and small amounts of interleukin (IL3) when stimulated with syngeneic or allogeneic accessory cells (AC) plus IL2. In contrast to the TcR pathway the alternative pathway does not require a rise of intracellular [Ca2+] and is insensitive to the effects of CsA. In this report we provide evidence for the involvement of T cell-stimulating factor (TSF)--a probably novel murine cytokine--in the alternative pathway of lymphokine production. It is shown that fixation of the AC with carbodiimide or treatment of the AC with UV light greatly reduces their capacity to induce (in combination with IL2) the synthesis of IFN-gamma by T cells. This function is restored by addition of TSF. Moreover, TSF alone (without IL2) in combination with fixed AC can induce the synthesis of substantial amounts of IFN-gamma. Furthermore, TSF in combination with IL2 can stimulate freshly isolated spleen cells to produce IFN-gamma. The target cell resides probably in the non-B cell, non-T cell population.
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PMID:Components of an antigen-/T cell receptor-independent pathway of lymphokine production. 190 19

Activation of protein kinase C (PKC) has been linked to the regulation of class II expression on endothelial cells by interferon-gamma (IFN-gamma). PKC subtypes in endothelial cells were analyzed using three different approaches, the immunoperoxidase staining of native and IFN-gamma stimulated cells cultured on chamber slides as well as immuno- and Northern blotting. All approaches revealed that of the conventional subtypes, alpha is the predominant form of PKC in endothelial cells. Even though IFN-gamma is able to induce PKC translocation to particulate fractions, no translocation was detected in histological stainings. Western blot studies as well as mRNA studies revealed that IFN-gamma is unable to increase the total amount of PKC in endothelial cells.
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PMID:Protein kinase C subtypes in endothelial cells. 190 74

Astrocytes can be induced by interferon-gamma (IFN-gamma) to express class II major histocompatibility complex (MHC) antigens. This study was undertaken to elucidate the intracellular signaling pathways involved in IFN-gamma induction of class II MHC. We examined the effects of Na+/H+ antiporter and protein kinase C (PKC) inhibitors on class II expression and Na+ influx in astrocytes. We found that amiloride and ethyl isopropylamiloride, inhibitors of Na+/H+ exchange, blocked IFN-gamma-induced class II gene expression. IFN-gamma stimulated Na+ influx, and this increased influx was inhibited by amiloride. Treatment of astrocytes with the PKC inhibitor H7 also blocked the increase in Na+ uptake induced by IFN-gamma, indicating that IFN-gamma-induced PKC activation is required for subsequent Na+ influx. IFN-gamma treatment produced an increase of total PKC activity, which was associated with a rapid translocation of PKC activity from cytosolic to particulate fraction. H7 and another PKC inhibitor, staurosporine, inhibited IFN-gamma-induced class II gene expression. However, 4 beta-phorbol 12 beta-myristate 13 alpha-acetate, a potent PKC activator, did not affect class II expression. Taken together, our data indicate that both IFN-gamma-induced PKC activation and Na+ influx are required for class II MHC expression in astrocytes but that activation of PKC alone is not sufficient for ultimate expression of this gene.
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PMID:Interferon-gamma-induced astrocyte class II major histocompatibility complex gene expression is associated with both protein kinase C activation and Na+ entry. 191 46

Synergy between ionomycin and sn-1,2-dioctanoylglycerol (diC8) was shown at the level of lymphokine gene transcription. Transcriptional activation of interleukin-2 (IL-2), interferon-gamma (IFN-gamma), and the protooncogene H-ras was accomplished by signaling highly purified normal human resting T-lymphocytes (T-cells) with diC8, a physiologic regulator of protein kinase C, and the calcium ionophore, ionomycin. Northern blot analysis of mRNA for early T-cell activation genes demonstrated the synergism between diC8 and ionomycin at the gene induction level. To amplify very low levels of IL-2 mRNA, sequential reverse transcription and polymerase chain reaction (RT-PCR) of T cell mRNA were used to demonstrate the capacity of the calcium signal (ionomycin) to promote low-level IL-2 transcription in normal human T-cells without additional signals. Cyclosporine (CsA) prevented diC8 and ionomycin-induced expression of IL-2, IFN-gamma, and H-ras genes. The completeness of its inhibitory effect was evident by the absence of IL-2 transcripts in CsA-treated cultures screened by the RT-PCR technique. CsA also prevented IL-2 and IFN-gamma gene expression in accessory cell-depleted T-cells stimulated by cross-linking the CD2 and CD3 antigens on the cell surface. Our observations demonstrate that a physiologic regulator of PKC, diC8, and cell surface crosslinking of the CD2 and CD3 antigen, promote gene expression in normal human quiescent T-cells independently of accessory cells, and that CsA prevents gene expression via a direct effect on T-cells.
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PMID:Physiologic signaling in normal human T-cells: mRNA phenotyping by northern blot analysis and reverse transcription-polymerase chain reaction. 197 31

Nuclear factor kappa B (NF-kappa B) is a ubiquitous transcription factor that affects expression of many genes, including immunoglobulin kappa (kappa), the interleukin-2 receptor alpha chain, and two genes in HIV-1. NF-kappa B can be activated by a number of stimuli, including pharmacological stimulation of protein kinase C by phorbol 12-myristate 13-acetate (PMA) and treatment in vitro with either protein kinase C or protein kinase A. This has lead to the proposal that these kinases are key enzymes in the physiological activation of NF-kappa B as well. We have used a murine B cell line, 70Z/3, and T cell line, EL-4 6.1 C10, to study the activation of NF-kappa B by two physiological activators, interleukin-1 alpha (IL-1) and lipopolysaccharide (LPS). There are four reasons to propose that these agents activate pathways that do not include protein kinase C as a major component in these cell lines. First, the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) strongly inhibited PMA-induced activation of NF-kappa B in 70Z/3 cells but had no effect on NF-kappa B activated by IL-1 or LPS. Second, depletion of protein kinase C by prolonged growth of 70Z/3 in PMA abrogated the capacity of the cells to activate NF-kappa B in response to further PMA treatment. However, these same cells activated NF-kappa B normally after either IL-1 or LPS treatment. Third, IL-1 effectively activated NF-kappa B in EL-4 6.1 C10 cells, but PMA did not. Fourth, interferon-gamma is a potent activator of protein kinase C in 70Z/3 cells, but is completely inactive in the mobilization of NF-kappa B. These results suggest that the physiological inducers IL-1 and LPS activate NF-kappa B by pathways independent of protein kinase C in both 70Z/3 and EL-4 6.1 C10 cells.
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PMID:Evidence that interleukin-1 and phorbol esters activate NF-kappa B by different pathways: role of protein kinase C. 205 61

AS101, a synthetic organotellurium compound, was found to have immunomodulating properties by initiation of cytokine production in vitro and in vivo. Phase I/II clinical trials currently in progress on AIDS and cancer patients treated with AS101 show significant increases in various immunological parameters, with minimal toxicity. Recently, AS101 and the protein kinase C (PKC) inducer, phorbol myristate acetate (PMA), were shown to synergize in the secretion of interleukin-2 (IL-2) and colony-stimulating factor (CSF) in vitro, by human and mouse lymphoid cells. The bryostatins, a group of natural macrocyclic lactones isolated from marine invertebrates (Bugula neritina) have been reported to be potent PKC activators with no tumour promoting activity. In this study, we investigated the synergistic effect of AS101 and a partially purified preparation of bryostatin on the production of several cytokines. Our data confirm the presence of synergism, which greatly enhances cell proliferation, IL-2, tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma) secretion by human mononuclear cells (MNC) and the production of IL-2 and TNF by mouse cells. The absence of tumour-promoting activity of the bryostatins makes them particularly good candidates, in combination with AS101, for immunomodulation in vivo in clinically immunosuppressed conditions.
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PMID:Cytokine secretion effected by synergism of the immunomodulator AS101 and the protein kinase C inducer bryostatin. 211 79


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