Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiofollicular lymph node hyperplasia is a heterogeneous disorder of unclear etiology and has a wide spectrum of systemic symptoms. This report describes a case of this disorder in a 15-year-old girl and examines the response of the primary mass, systemic symptoms, and alterations of selected immune parameters at diagnosis, as a result of steroid therapy and radiation therapy (RT). The patient had a 1-year history of growth failure, delayed puberty, and refractory iron deficiency anemia. Computed tomography scan showed a posterior mediastinal mass. Biopsy revealed angiofollicular lymph node hyperplasia of mixed hyaline-vascular and plasma cell type histologic type. Immunoperoxidase studies showed polyclonal B-cells, predominance of T-helper cells (CD4) over cytotoxic/suppressor T-cells (CD8), and the presence of natural killer (NK) cells. Southern blot analysis demonstrated germ line gene configuration for the T-cell antigen receptor and Ig heavy chain. The patient clinically improved with RT after failing to respond to steroids. Immunophenotyping of peripheral blood lymphocytes before therapy revealed a CD4:CD8 ratio of 0.8 with decreased numbers of circulating T-cells; this increased to 1.4 after steroid therapy. The patient's T-lymphocytes had no proliferative response to phytohemagglutinin (PHA) or concanavalin A (Con A) before RT. After RT, a small but significant mitogenic response to these reagents was noticed. The proliferative response to recombinant interleukin-2 (rIL-2) remained similar to that of control lymphocytes. Induction of second messenger signals by activation of protein kinase C (PKC) and elevation of free cytosolic calcium through the use of the phorbol ester, phorbol 12, 13-dibutyrate (PDBu), and ionomycin (Io) resulted in a strong proliferative response at diagnosis and after RT. In vitro cytotoxicity assays revealed diminished NK activity before and after therapy. Lymphokine-activated killer (LAK) activity remained comparable with that of control cells and was not affected by therapy. Before RT patient lymphocytes maintained cytotoxic capabilities after coincubation with rIL-2 and PDBu plus Io, whereas coincubation with these reagents abrogated cytotoxic function of normal cells. This case demonstrates a clinical response to RT as well as improvement in immune parameters. Intact signal transduction mechanisms through PKC activation and elevation of cytosolic calcium were also demonstrated in the circulating lymphocytes.
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PMID:Angiofollicular lymph node hyperplasia (Castleman's disease) in an adolescent female. Clinical and immunologic findings. 187 89

Responses to interleukin-2 (IL-2) of high-density human tonsillar B lymphocytes were examined in 20 microliters hanging drop microcultures. DNA synthesis and secretion of IgM and IgG were induced by IL-2 alone. Activation of calcium-dependent protein kinase C (PKC) with phorbol 12,13-dibutyrate and ionomycin increased IL-2 driven DNA synthesis yet reduced IL-2 driven secretion of IgM and IgG. Forskolin, which increases cAMP, had no effect on the responses to IL-2. Intrinsic IL-6 played no role in IL-2-induced DNA synthesis but was partially responsible for the secretion of immunoglobulin. These data show that pre-activation of the high-density human tonsillar B lymphocyte is not a prerequisite for IL-2-driven responses. They also show an asymmetry between the growth and differentiation induced by IL-2. This is reflected by opposite modulation on activation of PKC and by the role of the autocrine factor, IL-6.
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PMID:Interleukin-2-induced DNA synthesis and immunoglobulin secretion by resting human tonsillar B cells: effects of protein kinase C activation. 187 79

The phorbol ester TPA is a potent protein kinase C (PKC) activator and a cofactor in the activation of the human Jurkat leukemic T cell line. We have studied the implication of the PKC signaling pathway in the process of T cell activation by generating TPA resistant mutants of Jurkat. These mutants were obtained by recovery of cells that survived a growth arrest induced by TPA. Several cellular phenomena dependent on TPA were dramatically altered in the mutated cells. The mutants were unable to form homoaggregates upon TPA stimulation. Moreover, they did not produce interleukin-2 after activation through engagement of the T cell receptor, in the presence of TPA. These results suggest that the PKC signaling pathway activated by TPA is defective in these cells. In an attempt to define and locate the defect present in the mutants, we have analysed the biochemical properties of PKC, the cellular receptor of TPA. The increase in kinase activity and the translocation of the enzyme to the plasma membrane after stimulation by TPA appeared to be normal in the mutants. We hypothesize that a metabolic step, critical for the completion of T cell activation, distinct from protein kinase C, is impaired in the mutant cells.
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PMID:Isolation and characterization of a T lymphocyte mutant defective in the protein kinase C signal transduction pathway. 192 9

Immune regulation during syphilitic infection is extremely complex. This paper presents findings on the early events of T-cell activation following testicular infection in rabbits. Treponema pallidum was preincubated for 24 h with nonadherent spleen cells. After being washed to remove the organisms, these spleen cells were either stimulated with concanavalin A (ConA) to induce interleukin-2 (IL-2), or added to adherent cells that were then stimulated with lipopolysaccharide to induce IL-1. Preincubation with the treponemes up-regulated nonadherent cell functions. These sensitized cells increased their IL-2 production and augmented macrophage IL-1 synthesis. In sharp contrast, if this preincubation step was omitted, down-regulation was apparent. When T. pallidum was directly incubated with nonadherent cells in the presence of ConA, reduced levels of IL-2 were detected. Nonadherent cells from infected rabbits secreted soluble suppressive factors after 48 h of in vitro incubation; these factors inhibited ConA-induced IL-2 generation as well as ConA-induced lymphocyte proliferation. At least some of this suppressive activity was attributed to transforming growth factor. In addition, when T lymphocytes were depleted, less suppression was detected. Treponemes also inhibited ConA-induced T-cell proliferation, and monophosphoryl lipid A reversed this inhibitory effect. Since monophosphoryl lipid A neutralizes T-suppressor activity, these findings further suggest a role for T-suppressor activity during syphilitic infection. Finally, T. pallidum directly stimulated IL-2 synthesis when coincubated with phorbol myristate acetate. This agent reverses the prostaglandin E2 blockage of T-helper cell protein kinase C, a necessary second messenger signal for IL-2 synthesis. In summary, T-cell functions are extremely complex and represent a composite of both stimulation and down-regulation, which occur concurrently but to different degrees.
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PMID:Splenic T-lymphocyte functions during early syphilitic infection are complex. 193 75

Cultivation of human peripheral blood T-lymphocytes in the presence of interleukin-2 (IL-2) and phytohaemagglutinin (PHA) caused biphasic alterations in the beta 2-adrenoceptor density (Bmax) and cAMP content of these cells. The increase in Bmax after 18 h incubation with IL-2 and PHA was due to the expression of the receptors in a low-affinity state. The stimulatory effect of isoproterenol on adenylate cyclase activity and its effect on cAMP content remained unchanged, indicating uncoupling between the expressed receptors and regulatory Gs-proteins. The addition of phorbolmyristateacetate (PMA), a protein kinase C activator, also caused a biphasic change in beta 2-adrenoceptor density on the surface of the cells. The data point to the involvement of protein kinase C in the mechanism responsible for the increase and subsequent decrease in beta 2-adrenoceptor density seen after activation of T-lymphocytes.
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PMID:Alterations in beta-adrenoceptor density on T-lymphocytes upon activation with interleukin-2 and phytohaemagglutinin. 196 67

We investigated mechanisms by which the soluble native envelope glycoprotein gp120 of the human immunodeficiency virus (HIV-1) suppresses antigen-driven T cell responses. For this study, exogenous interleukin-2 (IL-2)-independent, antigen-specific, CD4 positive, human T-cell clones were developed by cyclic restimulation with soluble tetanus toxoid antigen. In the presence of soluble antigen and antigen-presenting cells (APC), T-cell clones proliferated and secreted IL-2. Purified gp120 suppressed the proliferative responses of the T-cell clones with concomitant suppression of IL-2 secretion; proliferative responses of CD8+ T cells preincubated with gp120 were not inhibited. A short pulse of 20 minutes with gp120 was sufficient to inhibit the proliferative response of the T-cell clones. Anti-CD3 monoclonal antibody (MoAb)-driven proliferation of the T-cell clones was also suppressed by gp120, but responses elicited by mitogens, phorbol myristate acetate (PMA) plus calcium ionophore, ionomycin, anti-CD2 MoAbs, and a combination of anti-CD3 plus anti-CD28 MoAb driven responses remained unaffected. Investigation of signal transduction events showed that antigen-driven early activation signals via translocation of protein kinase C (PKC), increase in intracellular inositol phosphates, and increase in intracellular calcium were suppressed in gp120 pretreated, tetanus toxoid antigen-stimulated T-cell clones. One mechanism of immune suppression by gp120 may involve interference with the initiation of signal transduction through the T-cell receptor complex.
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PMID:Inhibition of functional properties of tetanus antigen-specific T-cell clones by envelope glycoprotein GP120 of human immunodeficiency virus. 196 13

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

Peripheral blood mononuclear cells (PBMC) were cultured with phytohemagglutinin (PHA) in 46 colorectal cancer patients and 27 normal controls. By collectively comparing the cancer patients with the normal controls, the cancer patients had: (1) decreased interleukin-2 (IL-2) secretion, (2) fewer interleukin-2 receptor (IL-2R) expression on cell surface, and (3) less 3H thymidine incorporation. The ability of the phorbol ester, phorbol 12-myristate 13-acetate (PMA), and the calcium ionophore, A23187, in co-stimulation with PHA, to enhance the IL-2 secretion, IL-2R expression and 3H thymidine incorporation were studied in the PBMC of colorectal cancer patients. By adding A23187 into the PHA-stimulated PBMC from colorectal cancer patients, IL-2 production and IL-2R expression were increased up to levels equal to that obtained in PHA-stimulated PBMC from normal controls. Whereas there was no significant increase in proliferative response. However, PMA has no effect on all three parameters. A23187 is known to be effective in elevating cytosolic free Ca2+ and PMA is regarded as an activator of protein kinase C. Therefore, we may conclude that the impairment of IL-2 production and IL-2R expression in PHA-stimulated cultures is mainly due to failure of the free Ca2+ release which can be repaired by A23187. While protein kinase C activation may not be impaired since its deficit in IL-2 production and IL-2R expression can not be corrected by PMA.
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PMID:Proliferation, interleukin-2 production and receptor expression in peripheral blood mononuclear cells from colorectal cancer patients. 197 93

The present work investigated the association between prostaglandin E2 (PGE2) from macrophages and its inhibition of murine lymphokine-activated killer (LAK) cell generation. The coculture of indomethacin with interleukin-2 (IL-2) augmented LAK cell activity in an indomethacin dose-response manner, and diminished PGE2 content in the corresponding culture supernatant in a reverse dose-response manner. The correlation between the increase in LAK cell activity and the decrease in PGE2 content was highly significant. Identical results were obtained with diclofenac. A profound inhibition of LAK cell activity by exogenous PGE2 in a dose-response manner was detected. Polyclonal anti-PGE2 antiserum augmented in a dose-dependent manner the LAK cell activity, by neutralizing PGE2 in the medium. A reduction of PGE2 content in the culture supernatant was also detected when the macrophage subpopulations were cultured and was indomethacin dose-dependent. In comparison with that of normal mouse splenocytes, the incubation of whole splenocytes of tumor-bearing mice, which contained a greater subpopulation of macrophages (24% vs. 12%), produced a greater PGE2 content and a correspondingly depressed LAK cell activity. Additionally, PGE2 reduced protein kinase C (PKC) activity along with LAK cell activity generated from macrophage-depleted T cells and natural-killer-like cells. These results overall indicate that PGE2 from macrophages in murine splenocyte cultures inhibits the LAK cell generation, and PKC may be involved in the inhibition mechanism.
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PMID:Prostaglandin E2 from macrophages of murine splenocyte cultures inhibits the generation of lymphokine-activated killer cell activity. 202 83

The role of second messengers in the response of alloactivated T cells to growth factors (e.g., interleukin-2) is unknown. We have previously found that intracellular calcium may be an important T-cell alloactivation marker. To determine whether protein kinase C (PKC) is also involved in allosensitized T cell function, we studied the effects of the PKC agonists phorbol 12-myristate 13-acetate (PMA), mezerein (MEZ), and 1-oleoyl-2-acetylglycerol (OAG) and the PKC antagonists phloretin and D-sphingosine on the in vitro proliferation and migration of allosensitized cells from a C57BL/6 anti-DBA/2J mixed leukocyte culture (MLC). At 0.01-1.0 microgram/ml, PMA, a potent stimulant of PKC, exerted profound stimulatory effects on secondary MLC supernatant (2 degrees SN)-induced proliferation of allosensitized T cells (132-200% increase, P less than 0.01). Both MEZ and OAG are less potent activators of PKC than PMA but also stimulated T cell proliferation (132-152% of control, P less than 0.01). The PKC antagonists phloretin and D-sphingosine both inhibited proliferation by greater than 50% at 1.0-10.0 microM (P less than 0.01). Further experiments showed that these agents exert similar effects on in vitro T cell locomotion in a Boyden chamber assay. These data indicate that PKC activation may be an important component of allosensitized T cell proliferation and locomotion and may constitute a pathway by which T cell function may be modified in the allograft response.
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PMID:Evidence that protein kinase C regulates allosensitized T lymphocyte function. 205 67


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