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)

Activated polymorphonuclear leukocytes (PMNs), which are found in the inflammatory lesions of chronic inflammatory bowel disease, produce tissue-destructive oxygen-derived free radicals. The influence of 5-aminosalicylic acid (5-ASA), its acetylated metabolite (Ac-5-ASA), sulfasalazine (SAZ), and olsalazine (OLZ) (5-ASA dimer linked by an azo group) in pharmacologically relevant concentrations (0.1-10 mM) were tested on PMN superoxide production with either the receptor-specific agent formyl-methionyl-leucyl-phenylalanine (fMLP) or the protein kinase C activator phorbol myristate acetate (PMA). Inhibition of receptor-specific superoxide production occurred at 0.07, 0.32, and 0.63 mM (IC50 values) for 5-ASA, SAZ, and OLZ, respectively. No inhibitory effects of SAZ and OLZ were observed when PMA was applied as stimulus for PMN superoxide production. The results indicate that the signal to which PMNs respond by generating superoxide is primarily due to calcium release from intracellular stores. They further suggest that SAZ and OLZ may affect the oxygen-derived free radical production in human PMNs by unspecific cytotoxicity or by interference with the nicotinamide adenine dinucleotide phosphate, reduced (NADPH) oxidase system, whereas 5-ASA itself is a free radical scavenger.
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PMID:Effect of 5-aminosalicylic acid and analogous substances on superoxide generation and intracellular free calcium in human neutrophilic granulocytes. 810 Jun 41

A new, orally active de-N-acetylated lysoglycosphingolipid (WILD20) was evaluated as antiinflammatory agent using a model of chemically-induced inflammatory bowel disease (IBD) in the rat to mimic human ulcerative colitis and Chron's disease. IBD was induced by hapten trinitrobenzenesulphonic acid (TNB). WILD20, orally administered as preventive or curative, was demonstrated to be efficacious at daily dosages of 0.1-1 mg/kg for 4-5 days. Damage scores, body weight, spleen weight, colonic tissular levels of LTB4, myeloperoxidase (MPO) and malondialdehyde (MDA) are influenced and brought into parameters of normality. Histological observation demonstrated quicker healing, better repair, reduced inflammation, and poor eosinophil degranulation. The mechanisms underlying WILD20 antiinflammatory effects were investigated: whereas WILD20 fails to show a direct effect on PKC, it reduces PKC translocation to the membrane; cellular PLA2 was consequently greatly reduced through this mechanism and thought to be responsible for WILD20 efficacy towards chemically-induced IBD.
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PMID:Effect of a new de-N-acetyl-lysoglycosphingolipid on chemically-induced inflammatory bowel disease: possible mechanism of action. 813 10

The production of pro-inflammatory cytokines, such as interleukins 1 and 6 and tumour necrosis factors, occurs rapidly following trauma or invasion of the body by pathogenic organisms. The cytokines mediate the wide range of symptoms associated with trauma and infection, such as fever, anorexia, tissue wasting, acute phase protein production and immunomodulation. In part, the symptoms result from a co-ordinated response, in which the immune system is activated and nutrients released, from endogenous sources, to provide substrate for the immune system. Although the cytokine mediated response is an essential part of the response to trauma and infection, excessive production of pro-inflammatory cytokines, or production of cytokines in the wrong biological context, are associated with mortality and pathology in a wide range of diseases, such as malaria, sepsis, rheumatoid arthritis, inflammatory bowel disease, cancer and AIDS. Cytokine biology can be modulated by antiinflammatory drugs, recombinant cytokine receptor antagonists and nutrients. Among the nutrients, fats have a large potential for modulating cytokine biology. A number of trials have demonstrated the anti-inflammatory effects of fish oils, which are rich in n-3 polyunsaturated fatty acids, in rheumatoid arthritis, inflammatory bowel disease, psoriasis and asthma. Animal studies, conducted by ourselves and others, indicate that a range of fats can modulate pro-inflammatory cytokine production and actions. In summary fats rich in n-6 polyunsaturated fatty acids enhance IL1 production and tissue responsiveness to cytokines, fats rich in n-3 polyunsaturated fatty acids have the opposite effect, monounsaturated fatty acids decrease tissue responsiveness to cytokines and IL6 production is enhanced by total unsaturated fatty acid intake. There are a large number of potential cellular mechanisms which may mediate the effects observed. The majority relate to the ability of fats to alter the composition of membrane phospholipids. As a consequence of alterations in phospholipid composition, membrane fluidity may change, altering binding of cytokines to receptors and G protein activity. The nature of substrate for various signalling pathways associated with cytokine production and actions may also be changed. Consequently, alterations in eicosanoid production and activation of protein kinase C may occur. We have examined a number of these potential mechanisms in peritoneal macrophages of rats fed fats with a wide range of fatty acid composition. We have found that the total C18:2 and 20:4 diacyl species of phosphatidylethanolamine in peritoneal macrophages relates in a positive curvilinear fashion with dietary linoleic acid intake; that TNF induced IL1 and IL6 production relate in a positive curvilinear fashion to linoleic acid intake; that leukotriene B4 production relates positively with dietary linoleic acid intake over a range of moderate intakes and is suppressed at high intakes, while PGE2 production is enhanced. There was no clear relationship between linoleic acid intake and membrane fluidity, however fluidity was influenced in a complex manner by the type of fat in the diet, the period over which the fat was fed and the presence of absence of TNF stimulation. None of the proposed mechanisms, acting alone, can explain the positive effect of dietary linoleic acid intake on pro-inflammatory cytokine production. However each may be involved, in part, in the modulatory effects observed.
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PMID:Modulation of pro-inflammatory cytokine biology by unsaturated fatty acids. 955 30

Monocytic cells have been shown to produce endothelin, a potent vasoconstrictor molecule with immune modulating properties. The signalling mechanisms involved in this response are presently unclear. Monocytes are also believed to play an important role in inflammatory bowel disease (IBD). The objective of this study was to characterize the role of various cytokines, bacterial lipopolysaccharide (LPS) and colony-stimulating factors on the production of endothelin (ET) by freshly isolated human monocytes. Compelling circumstantial evidence exists for the conditions being investigated occurring in inflamed bowel mucosa to where monocytes migrate. Whereas LPS stimulated the release of 7 pg ET/2x106 cells in 40 hr, interferon-gamma (IFN-gamma) stimulated 45 pg ET/2x106 cells in 40 hr. There was an additive response when the two stimuli were employed together. Significantly the addition of either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) effected a two- to threefold, dose-dependent increase in the production of ET. Production of endothelin was reproducibly blocked by the addition of the protein kinase C (PKC) inhibitors staurosporine and H7, as well as by the protein synthesis inhibitor cycloheximide. Assessment of the activities of the alpha and beta isoforms of conventional protein kinase C (PKC), as determined by MonoQ column fractionated calcium and lipid activatible phosphotransferase activity towards myelin basic protein (MBP) revealed an additive effect of using LPS, IFN-gamma and GM-CSF, which was even greater than that demonstrated for phorbol myristate acetate (PMA). Additionally the secretion of ET by monocytes from Crohn's disease patients (in remission) was analysed and compared with an age-matched control group. There was no significant difference between the two. These results: (1) demonstrate an important synergistic role for GM-CSF and IL-3 in the predominantly IFN-gamma-mediated ET production by normal human monocytes; (2) indicate a possible role for the protein kinase C signalling pathway in this response; and (3) argue against a primary abnormality of ET production in peripheral monocytes from patients with Crohn's disease.
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PMID:Granulocyte-macrophage colony-stimulating factor and interleukin-3 potentiate interferon-gamma-mediated endothelin production by human monocytes: role of protein kinase C. 982 13

Using monolayers of human intestinal (Caco-2) cells, we found that oxidants and ethanol damage the cytoskeleton and disrupt barrier integrity; epidermal growth factor (EGF) prevents damage by enhancement of protein kinase C (PKC) activity and translocation of the PKC-beta1 isoform. To see if PKC-beta1 mediates EGF protection, cells were transfected to stably over- or underexpress PKC-beta1. Transfected monolayers were preincubated with low or high doses of EGF (1 or 10 ng/ml) or 1-oleoyl-2-acetyl-sn-glycerol [OAG; a PKC activator (0.01 or 50 microM)] before treatment with oxidant (0.5 mM H(2)O(2)). Only in monolayers overexpressing PKC-beta1 (3.1-fold) did low doses of EGF or OAG initiate protection, increase tubulin polymerization (assessed by quantitative immunoblotting) and microtubule architectural integrity (laser scanning confocal microscopy), maintain normal barrier permeability (fluorescein sulfonic acid clearance), and cause redistribution of PKC-beta1 from cytosolic pools into membrane and/or cytoskeletal fractions (assessed by immunoblotting), thus indicating PKC-beta1 activation. Antisense inhibition of PKC-beta1 expression (-90%) prevented these changes and abolished EGF protection. We conclude that EGF protection against oxidants requires PKC-beta1 isoform activation. This mechanism may be useful for development of novel therapies for the treatment of inflammatory gastrointestinal disorders including inflammatory bowel disease.
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PMID:PKC-beta1 mediates EGF protection of microtubules and barrier of intestinal monolayers against oxidants. 1151 96

5-Aminosalicylate, which is considered to be the active moiety of sulfasalazine, is one of the most widely used agents for treatment of inflammatory bowel disease. However, its mechanism of action is unclear. In this report, we provide evidence that the phospholipase D pathway is a target for this drug in macrophages. Activation of phospholipase D leads to the generation of important second messengers such as phosphatidic acid, lysophosphatidic acid and diacylglycerol, all of which can regulate cellular responses involved in inflammation. Murine peritoneal macrophages were labeled with [(3)H]myristate, incubated with various drugs, agonists, or inhibitors, and phospholipase D activity was assayed. 5-Aminosalicylate or sulfasalazine stimulated phospholipase D in a time- and concentration-dependent manner. Chelation of extracellular Ca(2+) inhibited phospholipase D activation by either of these drugs whereas pretreatment of macrophages with the tyrosine kinase inhibitor genistein had no effect. Downregulation of protein kinase C by prolonged incubation with phorbol ester completely blocked the activation of phospholipase D. Pertussis toxin decreased the activation of phospholipase D. The levels of inositol 1,4,5-trisphosphate increased by 260% after treatment of macrophages with 5-aminosalicylate. A phosphoinositide-specific phospholipase C inhibitor U73122 blocked phospholipase D activation completely. Interestingly, long-term preincubation of the macrophages with a relatively low concentration of 5-aminosalicylate that did not stimulate phospholipase D activity by itself, potentiated the effect of phorbol ester-induced activation of phospholipase D. Taken together, these results show that 5-aminosalicylate activates phospholipase D via a pathway involving inositol 1,4,5-trisphosphate generation, calcium fluxes, and Gi/Go. Although the mechanisms by which phospholipase D activation by 5-aminosalicylate or sulfasalazine might attenuate inflammatory responses in the intestine remain to be defined, these results highlight a novel potential mechanism of action for these drugs.
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PMID:5-Aminosalicylate stimulates phospholipase D activity in macrophages. 1156 48

Splice variants of the glycoprotein CD44 are transiently expressed on lymphocytes during T cell activation. Increased expression of CD44v6 on peripheral blood lymphocytes (PBL) of patients with inflammatory bowel disease (IBD) was described recently. The aim of this study was therefore to characterize CD44v6 expression on CD4(+) lamina propria lymphocytes (LPL) of patients with active IBD in comparison to controls. CD44v6 expression on CD4(+) LPL (n = 19) of controls and patients with active IBD (Crohn's disease n = 14, ulcerative colitis n = 15) was analyzed by flow cytometry and compared to that on autologous PBL. Thereby, in vitro regulation of CD44v6 on LPL and PBL via CD3 and CD2 and the costimulatory signal B7-1 was examined. In addition, the role of protein kinase C (PKC) in CD44v6 expression was tested. CD44v6 expression was increased in CD4(+) LPL (median, 45%) compared to PBL (median, 38%). Surprisingly, in IBD CD44v6 was downregulated on CD4(+) lamina propria T cells, irrespective of their state of inflammation (median, 28%). CD44v6 expression on LPL was not upregulated upon CD3 activation alone but following costimulation with B7-1. However, CD2-mediated T cell activation sufficiently induced upregulation of CD44v6 on LPL and PBL. In our study, downregulation of CD44v6 on LPL of patients with IBD was not due to defective PKC activation. Taken together, these data indicate that decreased CD44v6 expression on LPL in IBD might be a feature of an inappropriate costimulatory signal in T cell activation.
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PMID:Decreased CD44v6 expression in lamina propria lymphocytes of patients with inflammatory bowel disease. 1173 44

Using monolayers of intestinal (Caco-2) cells, we showed that oxidants disassemble the microtubule cytoskeleton and disrupt barrier integrity (permeability) (Banan et al., 2000a). Because exposure of our parental cells to oxidants causes protein kinase C (PKC)-delta to be translocated to particulate fractions, we hypothesized that PKC-delta activation is required for these oxidant effects. Monolayers of parental Caco-2 cells were incubated with oxidant (H(2)O(2)) +/- modulators. Other cells were transfected with an inducible plasmid to stably overexpress PKC-delta or with a dominant negative plasmid to stably inhibit the activity of native PKC-delta. In parental cells, oxidants caused translocation of PKC-delta to the particulate (membrane + cytoskeletal) fractions, activation of PKC-delta isoform, increases in monomeric (S1) tubulin and decreases in polymerized (S2) tubulin, disruption of the microtubule cytoarchitecture, and loss of barrier integrity (hyperpermeability). In transfected cells, induction of PKC-delta overexpression by itself (3.5-fold over its basal level) led to oxidant-like disruptive effects. Disruption induced by PKC-delta overexpression was potentiated by oxidants. Overexpressed PKC-delta resided in particulate fractions, indicating its activation. Stable inhibition of native PKC-delta activity (98%) by dominant negative transfection substantially protected against all measures of oxidative disruption. We conclude that 1) oxidants induce loss of intestinal epithelial barrier integrity by disassembling the microtubules in large part through the activation of the PKC-delta isoform; and 2) overexpression and activation of PKC-delta is by itself a sufficient condition for disruption of these cytoskeleton and permeation pathways. Thus, PKC-delta activation may play a key role in intestinal dysfunction in oxidant-induced diseases such as inflammatory bowel disease.
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PMID:Activation of delta-isoform of protein kinase C is required for oxidant-induced disruption of both the microtubule cytoskeleton and permeability barrier of intestinal epithelia. 1223 28

The activity of phospholipase A(2) (PLA(2)) is elevated in the intestinal epithelia of patients with inflammatory bowel disease. We recently reported that PLA(2) mediates the hydrolysis of phosphatidylcholine (PC) to lysophosphatidylcholine (L-PC) when both are applied to the apical surface of cultures enterocyte monolayers, resulting in increased bacterial translocation (BT) and decreased transepithelial electrical resistance (TEER). However, the mechanism by which the converted L-PC affects tight-junction permeability (TJP) as reflected by decreased TEER is unknown. There are some reports that protein kinase C (PKC) or Ca(2+) mediate TJP in enterocyte monolayer models. To investigate whether the observed change in TJP was mediated via PKC or Ca(2+) in our Caco-2 monolayer model, human Caco-2 enterocytes were grown to confluence on porous filters in the apical chamber of a two-chamber cell culture system. The filters were then transferred to an Ussing chamber for precise, real-time resistance measurements. After 30 min equilibration, PC (0.1 or 1 mM) and L-PC (0.01, 0.1 or 1 mM), PMA 200 or 300 nM (phorbol 12-myristate 13-acetate, PCK activator), or staurosporine 12 nM (PKC inhibitor) were added to the apical chamber and TEER was measured every 20 s for 2 h. The concentration of intracellular free Ca(2+) in the monolayers before and after treatment with L-PC (1 mM) was measured by fluorometry of whole monolayers using the fluorescent calcium indicator fura-2. Neither PC at any dose nor the 0.01-mM L-PC dose had an effect on TEER. The 0.1-mM dose of L-PC had its greatest effect (47% +/- 3.5% reduction in TEER vs control) within 6 min following its addition, with TEER recovery to control levels (100%) at 2 h ( P < 0.05). The 1-mM dose of L-PC had its greatest effect (6% +/- 0.5% reduction in TEER vs control) within 3 min after its addition, but the TEER did not recover to control levels after 2 h of incubation ( P < 0.05). The addition of 200 or 300 nM PMA inhibited the observed recovery of TEER by L-PC. Conversely, the addition of 12 nM staurosporine enhanced TEER recovery to control levels. The 1-mM dose of L-PC increased the concentration of intracellular free Ca(2+) immediately after the addition of L-PC. These results suggest that L-PC alters TJP via a PKC/Ca(2+) interaction in our Caco-2 monolayer model.
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PMID:Lysophosphatidylcholine alters enterocyte monolayer permeability via a protein kinase C/Ca2+ mechanism. 1247 72

Interleukin (IL) 6 is a pleiotropic cytokine (26 kDa) that originally was named interferon beta 2 or B cell-stimulating factor or differentiating B cell factor inducing immunoglobulin production. IL-6 is produced in many diseases. After secretion, IL-6 binds to its receptor IL-6R alpha (gp 80), the IL-6R alpha complex then recruits the signal-transducing beta-subunit (gp 130), which is the functional complex for signal transduction. In addition, activation of Th2 cells or mast cells also produce IL-6, which mediates immune responses, inflammation, acute phase responses, hematopoiesis, cancer, inflammatory bowel disease, etc. IL-6 also is a crucial cytokine for mast cell maturation. Human cord blood CD34+ cells differentiate and grow into mast cells in the presence of stem cell factor (SCF) and IL-6, causing increases in cell size, frequency of chymase positive cells, and intracellular histamine levels when compared with cells treated with SCF alone. Activated mast cells increase IL-6 mRNA associated with protein kinase C (PKC) activity. IL-6 also up-regulates histamine production rather than increases its storage and is an important inducing factor for the expression of immunoglobulin E (IgE) Fc epsilon RI.
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PMID:Interleukin-6 and mast cells. 1247 43


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