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)

The aim of this study is to clarify which signaling mechanism operates in Fc gamma receptor-mediated endocytosis in human neutrophils. Endocytosis of immune complexes was inhibited by antibodies directed to cell membrane phospholipase C (PLC) and A2 (PLA2) (maximal inhibition obtained was 57% and 28%, respectively), being almost abolished by these antibodies if used in combination (up to 91% inhibition). The protein kinase C (PKC) activator, phorbol 12,13-dibutyrate, reversed this inhibitory effect. Four different PKC inhibitors (H-7, palmitoylcarnitine, sphingosine, and tamoxifen) produced a dose-dependent inhibition of endocytosis, up to over 80% in each case. H-8 (1-10 microM) which inhibits cyclic nucleotide protein kinases but not PKC had no effect upon endocytosis. It is concluded that Fc gamma receptor-induced activation of PLC and PLA2 triggers endocytosis by activation of PKC.
 ...
PMID:Protein kinase C controls Fc gamma receptor-mediated endocytosis in human neutrophils. 214 63

In order to delineate structural-functional relationships of the mast cell receptor for IgE (Fc epsilon RI) by molecular-genetic analysis, a transfectable cell must be identified which resembles mast cells except for being deficient in receptors. We have found that the well known murine mastocytoma P815 is suitable. These cells express no Fc epsilon RI, lack mRNA for the alpha and beta subunits of the receptor, but contain some mRNA for gamma chains. After transfection with the cDNA for each of the subunits, stable clones could be isolated which expressed several hundred thousand normal Fc epsilon RI and synthesized large amounts of mRNA for alpha, beta, and gamma, the last at 3-fold higher levels than in the untransfected cells. Aggregation of the transfected receptors led to opening of presumptive calcium channels and to activation of phospholipase C, phospholipase A2, and protein kinase C. The kinetics and other characteristics of the signals were similar to those observed after stimulation of the rat tumor mast cells from which the receptor genetic material had been derived but were smaller in magnitude. These weaker signals most likely result from an overall reduced reactivity exhibited by the P815 cells since stimulation by other ligands led to weaker or even no responses. The cells failed to degranulate after either receptor aggregation or reaction with ionophores with or without phorbol ester. Both the transfected and untransfected P815 cells express Fc receptors for IgG (Fc gamma RII) which, interestingly, independently triggered similar responses despite their apparently simpler subunit structure.
 ...
PMID:Transmembrane signaling in P815 mastocytoma cells by transfected IgE receptors. 216 65

We investigated the positive and negative effects of IFN-gamma, PMA, dibutyryl cAMP (Bt2cAMP), dexamethasone and transforming growth factor-beta (TGF-beta) on Fc gamma R subtype expression and phagocytosis of a human monoblast cell line, U937. IFN-gamma increased and Bt2cAMP decreased Fc gamma RI expression determined by a mAb 32.2, whereas PMA and Bt2cAMP increased Fc gamma RII expression determined by a mAb IV-3. Phagocytosis was measured microscopically by counting ingested aggregated human IgG- or BSA-treated ox E (Eo'-IgG or Eo'-BSA). IFN-gamma increased the phagocytosis of Eo'-IgG but not that of Eo'-BSA, and PMA increased the phagocytosis of both Eo'-IgG and Eo'-BSA. Bt2cAMP decreased both basal and IFN-gamma- and PMA-augmented phagocytosis of U937 cells. Dexamethasone also inhibited both basal and IFN-gamma-augmented Fc gamma RI expression and PMA-augmented Fc gamma RII expression and phagocytosis, but did not affect IFN-gamma-augmented phagocytosis of Eo'-IgG. The augmentation of phagocytosis of Eo'-IgG by IFN-gamma thus seems to be due mainly to the increased internalizing process rather than to increased Fc gamma RI expression. TGF-beta slightly decreased Fc gamma R expression. In a study of the participation of protein kinase C (PK-C), it was found that H-7, a PK-C inhibitor, did not inhibit either IFN-gamma- or PMA-enhanced Fc gamma RI and Fc gamma RII expression, respectively, and 1-oleoyl-2-acetylglycerol and N-(6-phenylhexyl)-5-chloro-1-naphthalenesulfonamide, both PK-C activators, did not show any apparent increase in Fc gamma R expression and phagocytosis. These results show that Fc gamma RI and Fc gamma RII expression on U937 cells is regulated by different mechanisms and that IFN-gamma and PMA play their roles in Fc gamma R expression and phagocytosis by different pathways. It is possible that cAMP but not PK-C plays an important role in the regulation of Fc gamma R expression and phagocytosis.
 ...
PMID:Regulation of Fc gamma receptor expression and phagocytosis of a human monoblast cell line U937. Participation of cAMP and protein kinase C in the effects of IFN-gamma and phorbol ester. 255 78

The proliferative responses of natural killer (NK) cells to 12-O-tetradecanoylphorbol-13-acetate (TPA), which directly activates protein kinase c(PKC), and to the Ca2+ ionophores A23817 and ionomycin, known to enhance the intracellular calcium, have been investigated. Highly purified large granular lymphocytes (LGL) were cultured for 12-30 hr in the presence of TPA, ionomycin, or A23817. TPA alone (1-20 ng/ml) triggered rapid LGL proliferation, whereas the calcium ionophores were ineffective. The addition of either calcium ionophore to suboptimal doses or TPA (0.1-0.5 ng/ml) resulted in a synergistic effect on LGL proliferation. Under these conditions high levels of IL-2 activity were released by the LGL. Phenotypic analysis revealed the rapid loss of the Fc gamma receptors (CD16) on LGL and the induction of the expression of IL-2 (CD25) and transferrin receptors and of HLA-DR, but not of CD3. Removal of extracellular Ca2+ by addition of EGTA at the beginning of the culture greatly depressed LGL proliferation and IL-2 production, and blocked phenotypic changes, such as the expression of Tac antigen. Finally, progression to the proliferative phase of LGL, activated by TPA alone or with ionomycin, was completely abrogated by a hyperimmune anti-IL-2 antiserum.
 ...
PMID:Proliferative effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) and calcium ionophores on human large granular lymphocytes (LGL). 283 70

We have shown previously that normal human neutrophils triggered by immune complexes displayed significant levels of cytotoxicity towards non-sensitized target cells (non-specific cytotoxicity-NSC) (Geffner, J. R. et al. 1987). Despite the fact that NSC and antibody-dependent cellular cytotoxicity (ADCC) are both mediated through neutrophil Fc gamma R and require the activation of the respiratory burst, the cytolytic mechanisms involved in each case appear to be different. In order to analyse the pathways of activation involved in the induction of NSC and ADCC, we studied here some of the metabolic requirements associated with each cytotoxic function. Our results suggest that ADCC is dependent on Na+/H+ antiporter activity, de novo protein synthesis, availability of external Ca2+ and calmodulin activity, activation of phospholipase C and activation of protein kinase C. On the other hand, NSC appears to be dependent on availability of external Ca2+ and calmodulin activity and activation of phospholipase A2. These results indicate that different pathways of activation are involved in the induction of neutrophil-mediated ADCC and NSC.
 ...
PMID:Different activation pathways involved in antibody-dependent and immune-complexes-triggered cytotoxicity mediated by neutrophils. 285 17

A protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), inhibited phorbol ester (12-o-tetradecanoylphorbol 13-acetate)-induced and Fc gamma receptor-mediated superoxide anion (O2-) generations in guinea pig macrophages, but the inhibitory effect on Fc gamma receptor-mediated O2- generation was only partial. Both O2- generations were inhibited extensively by a phospholipase A2 inhibitor, 4-p-bromophenacyl bromide (4-pBPB). It was confirmed in control experiments that H-7 and 4-pBPB had no direct inhibitory effect on NADPH-oxidase activity. Dose-dependent stimulation of O2- generation was induced by arachidonate in macrophages, and the arachidonate-induced O2- generation was not inhibited by H-7. Arachidonate could also induce NADPH-oxidase activation in a post-nuclear fraction obtained from unstimulated macrophages and this activation was not inhibited by H-7, indicating that protein kinase C activation was not involved in this cellfree system. These results support the hypothesis that the O2- generation induced by Fc gamma receptor stimulation is mainly mediated by arachidonic acid which is released by the action of phospholipase A2 activated by receptor stimulation. Arachidonic acid seems to be acting rather directly in activating the NADPH-oxidase system of macrophage membrane. Protein kinase C may have a significant role in Fc gamma receptor-mediated O2- generation but it is not obligatory, and protein kinase C seems to activate NADPH-oxidase rather indirectly, probably by inducing the arachidonic acid release.
 ...
PMID:Arachidonic acid acts as an intracellular activator of NADPH-oxidase in Fc gamma receptor-mediated superoxide generation in macrophages. 303 22

CD43 is a cell-surface sialoglycoprotein which is selectively expressed on lympho-haemopoietic cells. We studied the effects of three CD43 antibodies (6E5, 6F5 and 10G7) on human neutrophils and found that all three monoclonal antibodies (mAb) induced significant homotypic adhesion involving more than 50% of cells. Monovalent Fab fragments of CD43 mAb had no such effect but became equally effective upon cross-linkage with F(ab')2 sheep anti-mouse immunoglobulin (Ig) antibodies. The homotypic adhesion induced by CD43 antibodies was dependent on divalent cations, energy, temperature and an intact cytoskeleton, but not on de novo protein synthesis. Homotypic adhesion could be inhibited by mAb to CD11b, CD18 and CD54, indicating an involvement of the beta 2 integrin cyto-adhesion pathway. Additionally, oxidative burst formation was observed with intact CD43 mAb. No such effect was seen with monomeric or cross-linked Fab fragments. This, together with the observation that burst formation unlike adhesion induction could be completely abolished with Fc gamma RII, but not with Fc gamma RIII antibody fragments, suggests that in burst induction, heterologous cross-linkage with Fc gamma RII is involved. A Ca2+ increase with CD43 antibodies was not detectable. Adhesion induction was unaffected by H7, chelerythrin, staurosporine or lavendustin A, but was completely ablated by sphingosine and herbimycin A. This suggests an involvement of tyrosine kinases but not of protein kinase C in the signal transduction cascade leading to homotypic adhesion. CD43 mAb-induced burst formation differed from adhesion induction in that it could be additionally inhibited with staurosporine and lavendustin A.
 ...
PMID:Induction of neutrophil homotypic adhesion via sialophorin (CD43), a surface sialoglycoprotein restricted to haemopoietic cells. 750 92

The effects of ketotifen fumarate (KF) and clemastine fumarate (CF) on neutrophil chemiluminescent (CL) responses to zymosan particles coated with either IgG (IgGZ), C3 (C3Z), or both (IC3Z), were examined in vitro. These opsonized zymosans caused not only detectable neutrophil superoxide anion generation evaluated by an MCLA-dependent CL (MDCL) assay, with the order of light emission being IC3Z > IgGZ > C3Z, but also a transient rise of neutrophil [Ca2+]i measured by an aequorin-dependent CL (ADCL) assay. Both KF and CF could suppress all opsonized zymosan-induced neutrophil MDCL in a dose-dependent fashion, but not all ADCL. Similar inhibitory effects of KF and CF were observed on the phorbol myristate acetate-induced MDCL. However, there was no interference by these two drugs with the measurement of MDCL in the hypoxanthine/xanthine oxidase superoxide anion generation system. These results indicate that the inhibitory effects of both KF and CF on Fc gamma R- and/or CR-mediated neutrophil oxidative potential is attributable to effects on an enzymatic reaction after protein kinase C activation in the oxidative signal transduction pathway.
 ...
PMID:Inhibition of Fc gamma R- and CR-mediated human neutrophil chemiluminescent responses by anti-allergic and anti-histaminergic drugs. 756 65

Human neutrophils are able to kill in vitro colorectal carcinoma cell line SW11-16 coated with mAb 17-1A, but they are not cytotoxic towards a non-immunized tumour target. Neutrophil exposure to the inflammatory cytokine, IL-8, produces a significant increase in antibody-dependent cellular cytotoxicity, which is related to IL-8 concentration. Oxyradical production is one of the lytic mechanisms used by phagocytes, and IL-8 is shown to activate this function, which does not occur if neutrophils are pretreated with the protein kinase C inhibitor, staurosporine, but is increased by R59022, a dyacylglycerol kinase inhibitor. The IL-8 effect is mediated by protein kinase C, which is potentiated by the calcium flux induced by the interaction between antibody coating tumour target and Fc gamma RIII on effector cells, as previously demonstrated. Data suggest a possible new role for IL-8 in tumour surveillance.
 ...
PMID:IL-8 enhances antibody-dependent cellular cytotoxicity in human neutrophils. 759 Aug 96

Intracellular killing of Staphylococcus aureus by human monocytes after cross-linking Fc gamma R is known to be a phospholipase C (PLC)-dependent process. Activation of PLC leads to the formation of second messengers that synergistically activate protein kinase C (PKC). The aim of this study was to obtain more insight into the role of PKC in Fc gamma R-mediated killing process. PKC inhibitors H-7 and staurosporine markedly suppressed the killing of S. aureus by monocytes stimulated by cross-linking Fc gamma RI or -II. Cross-linking Fc gamma R caused a transient increase in PKC activity in the membranes of monocytes, as measured by Ca2+/phospholipid-dependent phosphorylation of histone. Western blot analysis revealed that cross-linking Fc gamma R stimulated a transient increase in PKC-beta in the membranes of monocytes with kinetics that correlated closely with the translocation of PKC activity. Cross-linking Fc gamma R on monocytes also stimulated the translocation of PKC-epsilon but not PKC-alpha. PMA and 1-oleoyl-2-acetylglycerol (OAG), which caused translocation of PKC-alpha, -beta, and -epsilon, did not stimulate the killing process. Incubation with these PKC activators for 10 min rendered monocytes unresponsive to stimulation of killing of S. aureus via Fc gamma R. It could be that activation of certain PKC isozymes, probably PKC-alpha and -epsilon, by these activators causes feedback inhibition of PLC and, consequently, the killing in monocytes, because PMA blocks the Fc gamma R-mediated intracellular inositol(1,4,5)P3 formation and PKC translocation. Together, our results indicate that PKC isozymes play an important role in both stimulation and inhibition of the Fc gamma R-mediated intracellular killing of bacteria by monocytes.
 ...
PMID:Role of protein kinase C isozymes in Fc gamma receptor-mediated intracellular killing of Staphylococcus aureus by human monocytes. 760 54


<< Previous 1 2 3 4 5 Next >>