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)

Among the cytokines tested here (IL-2, IL-3, IL-4, IL-5, IL-6, granulocyte colony stimulating factor (G-CSF), granulocyte/macrophage colony stimulating factor (GM-CSF), interferon-alpha (IFN-alpha), interferon-beta (IFN-beta) and interferon-gamma (IFN-gamma] only interleukin 1(IL-1) augmented HIV-long terminal repeat(LTR) directed chloramphenicol acetyl transferase(CAT) activity in protein kinase C(PKC)-independent manner. However, a stimulation by IL-1 was not as efficient as that due to tumor necrosis factor and the HIV production was not significant. IL-1 was not cytotoxic to MOLT-4/HIV cells.
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PMID:Effect of interleukin-1 on the augmentation of human immunodeficiency virus gene expression. 248 Jul 82

Eosinophils are known to play an important role in the pathogenesis of asthma and other allergic diseases. This study demonstrated the effects of various drugs on eosinophil viability in vitro, which might help clinicians and researchers in treating and studying eosinophilic diseases. Staurosporine, a protein kinase C inhibitor, and herbimycin A, a tyrosine kinase inhibitor, at 10(-6) M and 10(-7) M significantly lowered eosinophil viability in a dose-dependent fashion (p < 0.002, p < 0.02 and p < 0.001, p < 0.002, respectively). Both staurosporine and herbimycin A reduced eosinophil survival in a time-dependent fashion at 10(-6) M and 10(-7) M. Ketotifen at 10(-4) M and theophylline at 10(-3) M, significantly decreased eosinophil viability (p < 0.001 and p < 0.001, respectively) in the presence of 100 pg/ml of recombinant human interleukin-5 (rhIL-5). Both FK506 and cyclosporin A at 10(-4) M significantly reduced eosinophil viability (p < 0.001 and p < 0.005, respectively) in the presence of 100 pg/ml of rhIL-5. Our data show that ketotifen, theophylline, FK506, cyclosporin A reduced eosinophil viability at a high concentration. Furthermore, it is suggested that protein kinase C and tyrosine kinase are involved in eosinophil survival.
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PMID:Effects of various drugs (staurosporine, herbimycin A, ketotifen, theophylline, FK506 and cyclosporin A) on eosinophil viability. 752 Jun 89

IL-5 was produced in vitro by peripheral blood mononuclear cells (PBMC) of mite-sensitive atopic patients upon challenge with specific allergen, while PBMC of healthy controls produced essentially no IL-5. Stimuli delivered by the combination of phorbol ester and Ca2+ ionophore induced marked IL-5 production by PBMC obtained from atopic and non-atopic asthmatics, suggesting that both protein kinase C and Ca2+ influx are required for IL-5 production. CD2- or CD4-bearing cell depletion almost completely removed IL-5-producing cells while CD8-bearing cell depletion rather enriched them. These findings indicate that CD4+ T cells are the principal source of IL-5 in PBMC. The capacity of PBMC of atopic asthmatics, non-atopic asthmatics and healthy controls to produce IL-2, IL-4, IL-5 and IFN-gamma was compared, to find that cytokine-producing capacities other than that of IL-5 (IL-2, IL-4 and IFN-gamma) were not significantly different among the three groups. Dexamethasone, FK506 and cyclosporin A suppressed IL-5 production in vitro in a dose-dependent manner. Clear dose-dependent suppression of IL-5 gene expression by FK506 was also observed. Treatment of asthmatic patients with inhaled glucocorticoid (beclomethasone dipropionate) ameliorated clinical symptoms, improved lung function and markedly suppressed IL-5 production by PBMC, suggesting the essential role of IL-5 in the pathogenesis of bronchial asthma and the clinical importance of its regulation.
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PMID:IL-5 production by CD4+ T cells of asthmatic patients is suppressed by glucocorticoids and the immunosuppressants FK506 and cyclosporin A. 754 Aug 62

In the present study, we have used a human erythroleukemia cell line, TF-1, that proliferates in response to granulocyte macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5) to investigate the role of receptors for these cytokines in signal transduction mechanisms involved in proliferative responses. The receptors for GM-CSF, IL-3, and IL-5 each possess a cytokine specific alpha subunit, but all three share a common beta chain. Using an immunoblotting system designed to detect phosphotyrosine containing proteins and a permeabilized cell system to detect rapid changes in phosphate turnover on proteins, we show that while GM-CSF and IL-3 use tyrosine phosphorylation to mediate mitogenic signal transduction, IL-5 uses tyrosine dephosphorylation in its signaling pathway. The use of different signaling pathways by these cytokines can be confirmed in a biologic system whereby the proliferation induced in culture by GM-CSF and IL-3 is inhibited by tyrosine kinase inhibitors, but that induced by IL-5 is enhanced. Conversely, GM-CSF- and IL-3-induced proliferation is stimulated by a tyrosine phosphatase inhibitor, yet IL-5-induced proliferation is inhibited. Inhibitors of protein kinase C inhibit IL-3- and GM-CSF-, but not IL-5-induced proliferation. We suggest that, because all these cytokines share the identical beta chain of their receptors, the cytokine specific alpha chain mediates the linkage of each receptor to the individual biochemical signal transduction pathways responsible for the different biologic activities of these cytokines.
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PMID:Evidence for a signaling role for the alpha chains of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 receptors: divergent signaling pathways between GM-CSF/IL-3 and IL-5. 754 66

Very recently, an AP3-like transcription factor regulating the chemokine gene MARC and an NF-AT family member regulating IL-5 were the first components of the transcription factor repertoire to be described as activated in mast cells after an allergic triggering. In this study, we show that with respect to cross-competition in a gel shift analysis using an NF-AT consensus oligonucleotide binding site, the antigenicity to a recently generated serum against T cell NF-AT, and the sensitivity to macrolide immunosuppressants, the AP3-like activity on the MARC promoter is indistinguishable from that described for NF-AT in T cells. Additionally, we show that this factor functions on the MARC chemokine promoter without the AP1 cofactor, a situation reminiscent of the function of NF-AT in Th2-type T cells. In all of these aspects, and strengthened further by a gel shift competition analysis, the AP3-like transcription factor is identical to the NF-AT family member recently described by an analogous set of experiments as regulating IL-5 in mast cells. Our finding that p21ras, but probably not protein kinase C, is necessary to activate this factor after Fc epsilon RI triggering indicates a situation in which a common transcription factor denominator in mast cells induces chemokine (MARC) and lymphokine (IL-5) gene expression in a manner closely similar to Th2-type T cells, which are induced along the ras/raf signal pathway.
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PMID:p21ras links Fc epsilon RI to NF-AT family member in mast cells. The AP3-like factor in this cell type is an NF-AT family member. 759 2

A 2-year-old female with important signs of immune response failure against virus, bacteria, fungi and protozoa and no obvious humoral or lymphocyte phenotypical defect was studied. Both peripheral blood mononuclear cells and IL-2-dependent T cell lines derived from the patient showed a severe selective T cell activation impairment via CD2, CD3 and CD43; however, this defect was reversible with the addition of either IL-2, or phorbol myristate acetate (PMA) or anti-CD28 antibodies. Concordantly, the induction of IL-2 (and, in part, IL-3 and IL-4) messenger RNA was severely reduced in stimulated T cells, but that of other cytokines was either normal (IL-5) or only slightly diminished (interferon-gamma (IFN-gamma)). It is concluded that an activation T cell defect exists previous to protein kinase C (PKC) and between membrane receptors and the activation pathway of certain response genes encoding for interleukins involved in proliferation (i.e. IL-2, IL-3 and IL-4), but not of others (i.e. IL-5). The use of T cell lines from human T lymphocyte activation deficiencies allows dissection of T cell pathology and the corresponding physiological pathways. In the present description, there is an evident independence of the CD28 T cell activation pathway from those induced through CD2 or CD3, and the differential gene regulation of the different interleukins.
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PMID:Primary T lymphocyte immunodeficiency associated with a selective impairment of CD2, CD3, CD43 (but not CD28)-mediated signal transduction. 791 76

This review concerns the regulation of expression of the two main eosinophil differentiating factors, interleukin-5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The latter, GM-CSF, is expressed in a wide variety of differentiated and non-differentiated cell types: T cells, monocytes, macrophages, fibroblasts, and endothelial cells. On the other hand, IL-5 is only expressed by a limited number of fully differentiated cells: eosinophils, mast cells, and a subset of T cells. Activation of GM-CSF in T cells and non-T cells occurs by different mechanisms, regulated both transcriptionally and post-transcriptionally. The transcriptional activation of GM-CSF via protein kinase C pathway and via viral transactivating proteins involves different regulatory elements of its promoter. Although one of these cis acting elements is common to IL-5, the activation of IL-5 apparently proceeds via different mechanism(s).
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PMID:Regulation of interleukin-5 and granulocyte-macrophage colony-stimulating factor expression. 795 92

The effects of prostaglandin E2 (PGE2) on cytokine production and proliferation of the CD4+ human helper T cell clone SP-B21 were investigated. In cells stimulated with anti-CD3 mAb, PGE2 inhibited cell proliferation and the production of all the cytokines examined. Addition of rIL-2 fully restored the proliferative response and partially restored the production of IL-4 and IL-5, but not that of other cytokines. In contrast, in cells stimulated with phorbol myristate acetate (PMA)/A23187, PGE2 enhanced the production of IL-4 and IL-5, and only partially inhibited the production of other cytokines. Therefore, the effects of PGE2 vary depending on the mode of T cell activation, and the IL-4 and IL-5 are regulated differently from other cytokines. In a mobility shift assay, only the NF-kappa B (p50/p50) homodimer was observed in a complex formed with the kappa B sequence in unstimulated SP-B21 cells. When cells were stimulated with anti-CD3 mAb or PMA/A23187, a complex formation of NF-kappa B (p50/p65) heterodimer with the kappa B sequence was induced. Interestingly, PGE2 or di-butyryl (Bt2)cAMP abolished the binding of NF-kappa B (p50/p65) heterodimer to the kappa B sequence in cells stimulated with anti-CD3 mAb but not with PMA/A23187. Our results suggest that the target of PGE2 action is a component in the signal transduction pathway leading to the activation of protein kinase C. However, the inhibition of the T cell activation signals by PGE2 is selective. PGE2 enhanced the complex formation with NF-AT, AP-1 and CLE0 sequences when the cells were activated by either anti-CD3 mAb or PMA/A23187 stimulation. It seems therefore that PGE2, by elevating cAMP levels, interferes with the activation pathway for NF-kappa B but not for NF-AT, AP-1 or CLE0 binding protein.
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PMID:Effects of prostaglandin E2 on Th0-type human T cell clones: modulation of functions of nuclear proteins involved in cytokine production. 801 94

Secretion of unique eosinophil granule constituents may play a role in allergic and parasitic reactions. Therefore we have investigated possible mechanisms for regulation of secretion in eosinophils. A hemolytic plaque assay and an enzyme-linked immunospot (ELISPOT) assay were developed for detection of secreted eosinophil cationic protein (ECP) from single adherent eosinophils. The protein kinase C activator phorbol 12-myristate 13-acetate (PMA) induced release of ECP in a dose-dependent fashion but 4-alpha-PMA, an analogue that does not activate protein kinase C, did not cause degranulation. Staurosporine and K252a, inhibitors of protein kinase C, decreased PMA-induced ECP secretion. Low concentrations of cytochalasin B enhanced PMA-induced secretion but high concentrations had an inhibitory effect. The calcium ionophores A23187 and ionomycin were weaker secretagogues than PMA. Tumor necrosis factor, granulocyte-macrophage colony-stimulating factor, interleukin-3, interleukin-5, N-formylmethionyl-leucyl-phenylalanine, and lipopolysaccharide caused little or no degranulation in adherent eosinophils. Preincubation of eosinophils with antibodies to CD18, the common beta chain of leukocyte adhesion proteins, resulted in inhibition of PMA-induced ECP release from adherent cells. 1,2-Bis(O-aminophenyl)-ethane-ethane-N,N,N',N'-tetraacetic acid (BAPTA), an agent that acts intracellularly by chelation of calcium, also inhibited PMA-mediated ECP release. In conclusion, PMA induces release of ECP from single adherent eosinophils and the effect appears to be mediated via protein kinase C and, in contrast to that in neutrophils, to be dependent on CD11/CD18 leukocyte integrins.
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PMID:Phorbol ester-induced degranulation in adherent human eosinophil granulocytes is dependent on CD11/CD18 leukocyte integrins. 809 65

The effects of CGP 41251, a specific inhibitor of protein kinase C (PKC), its inactive derivative CGP 42700, and of staurosporine have been analyzed in vitro on T lymphocyte functions. The proliferation of fresh human peripheral blood lymphocytes stimulated with antigen (PPD) or anti-CD3 mAb was strongly inhibited by both staurosporine (IC50 < 0.01 microM) and CGP 41251 (IC50 = 0.092 microM) but not by the PKC inactive compound CGP 42700 (IC50 > 10 microM). Antigen-specific activation and proliferation of mouse lymph node T cells was inhibited by staurosporine and CGP 41251 with IC50 values of 0.008 and 0.05 microM, respectively. The inactive derivative caused 50% inhibition in this mouse T cell assay only at concentrations of 25 microM. In order to evaluate possible differential effects of PKC inhibitors on CD4+ T cell subsets, murine T helper cell type 1 (Th1) and type 2 (Th2) clones were used. The KLH-specific clone 9/6 secretes IL-2 and IFN-gamma (Th1), whereas clone 9A/B does not secrete these lymphokines but secretes IL-4 and IL-5 (Th2). It was found that CGP 41251 inhibited antigen-induced proliferation of both Th1 and Th2 equally well with an IC50 of 0.02 microM. Furthermore, CGP 41251 inhibited the IL-2 or IL-2 and IL-4-mediated growth of Th1 and Th2 cells (IC50, 0.08 and 0.02 microM, respectively). Moreover, CGP 41251, but not CGP 42700, inhibited antigen-specific killing of target cells by Th1 clones (IC50 = 0.2 microM), a phenomenon which does not require cell proliferation. When Th1 cells were preincubated with the compound, washed, and rested for 24 hr, they killed the target cells, whereas killing by similarly preincubated, washed, but not rested Th1 cells was inhibited. Thus, the inhibitory effect of CGP 41251 is reversible and excludes the possibility of inhibition due to toxicity at the IC50 dose given. The comparison of CGP 41251 and staurosporine showed that although CGP 41251 has lower activity, it is more specific and much less toxic than staurosporine. Thus, CGP 41251 is more suitable for PKC studies.
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PMID:Effects of a new protein kinase C inhibitor CGP 41251 on T cell functions: inhibition of activation, growth, and target cell killing. 810 85


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