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At least 829 records · Page 46Linked to original sources
PubMed1995

Inhibition of the arachidonic acid pathway prevents induction of IL-8 mRNA by phorbol ester and changes the release of IL-8 from HL 60 cells: differential inhibition of induced expression of IL-8, TNF-alpha, IL-1 alpha, and IL-1 beta.

The promyelocytic HL 60 cell line can be used as an in vitro model system to study hematopoetic cell differentiation and inflammatory events. We studied the signal transduction pathway of induced interleukin (IL)-8 expression and compared it with those of tumor necrosis factor alpha (TNF-alpha), IL-1 alpha, and IL-1 beta. The differentiation of HL 60 cells to macrophage-like cells by PMA resulted in a rapid and marked induction of these inflammatory cytokines. The up-regulation occurred in the absence of ongoing protein synthesis, but cycloheximide-sensitive gene products modulated their induction kinetics. Staurosporine, a potent inhibitor of protein kinases, strongly inhibited their gene expression. Phosphorylation may not act directly on latent transcription factors, since bromophenacyl bromide, an inhibitor for the release of arachidonic acid from phorbol-12 myristate 13-acetate (PMA)-stimulated HL 60 cells, markedly depressed the induced mRNAs for IL-8, TNF-alpha, and IL-1 alpha and -beta. Similarly, 5,8,11,14 eicosatetraynoic acid (ETYA), another inhibitor of the arachidonic acid pathway, blocked the induction of transcripts for TNF-alpha, and both IL-1 genes in phorbol ester-stimulated HL 60 cells. In contrast, ETYA increased the induced IL-8 RNA levels and stimulated the release for IL-8. Also, ketoconazole, an inhibitor of 5-lipoxygenase and indomethacin, an inhibitor of cyclooxygenases did not block the induction of IL-8 mRNA. However, the release of IL-8 protein was regulated by indomethacin and ketoconazole. Our results indicate that arachidonic acid metabolites are mediators in the signal transduction pathway of IL-8 expression and that the involved second messengers are different from those which are important for the induction of TNF-alpha and IL-1 beta expression.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed2006

BK-induced cytosolic phospholipase A2 expression via sequential PKC-delta, p42/p44 MAPK, and NF-kappaB activation in rat brain astrocytes.

Bradykinin (BK), an inflammatory mediator, has been shown to induce cytosolic phospholipase A2 (cPLA2) expression implicating in inflammatory responses in various cell types. However, the detailed mechanisms underlying BK-induced cPLA2 expression in astrocytes remain unclear. RT-PCR and Western blotting analysis showed that BK induced the expression of cPLA2 mRNA and protein, which was inhibited by Hoe140, suggesting the involvement of B2 BK receptors, confirmed by immunofluorescence staining using anti-B2 BK receptor antibody. BK-induced cPLA2 expression and phosphorylation of p42/p44 MAPK was attenuated by PD98059, indicating the involvement of MEK1/2-p42/p44 MAPK in these responses. BK-induced cPLA2 expression might be due to the translocation of NF-kappaB into nucleus which was inhibited by Hoe140, helenalin, and PD98059, implying the involvement of NF-kappaB. Moreover, BK-induced cPLA2 expression was attenuated by rottlerin, suggesting that PKC-delta might be involved in these responses. This hypothesis was supported by the transfection with a dominant negative plasmid of PKC-delta significantly attenuated BK-induced response. In addition, BK-stimulated translocation of PKC-delta from cytosol to membrane fraction was inhibited by rottlerin but not by PD98059, indicating that PKC-delta might be an upstream component of p42/p44 MAPK. Accordingly, BK-induced phosphorylation of p42/p44 MAPK was attenuated by rottlerin but not by helenalin. These results suggest that in RBA-1 cells, BK-induced cPLA2 expression was sequentially mediated through activation of PKC-delta, p42/p44 MAPK, and NF-kappaB. Understanding the regulation of cPLA2 expression induced by BK in astrocytes might provide a new therapeutic strategy of brain injury and inflammatory diseases.

Acetophenones↗
PubMed2007

Potent stimulation of large-conductance Ca2+-activated K+ channels by rottlerin, an inhibitor of protein kinase C-delta, in pituitary tumor (GH3) cells and in cortical neuronal (HCN-1A) cells.

The effects of rottlerin, a known inhibitor of protein kinase C-delta activation, on ion currents were investigated in pituitary tumor (GH3) cells. Rottlerin (0.3-100 microM) increased the amplitude of Ca2+-activated K+ current (I K(Ca)) in a concentration-dependent manner with an EC50 value of 1.7 microM. In intracellular perfusion with rottlerin (1 microM) or staurosporine (10 microM), phorbol 12-myristate 13-acetate-induced inhibition of I K(Ca) in these cells was abolished. In cell-attached mode, rottlerin applied on the extracellular side of the membrane caused activation of large-conductance Ca2+-activated K+ (BK(Ca)) channels, and a further application of BAPTA-AM (10 microM) to the bath had no effect on rottlerin-stimulated channel activity. When cells were exposed to rottlerin, the activation curve of these channels was shifted to less positive potential with no change in the slope factor. Rottlerin increased BK(Ca)-channel activity in outside-out patches. Its change in kinetic behavior of BK(Ca) channels is primarily due to an increase in mean open time. With the aid of minimal kinetic scheme, a quantitative description of rottlerin stimulation on BK(Ca) channels in GH3 cells was also provided. Under current-clamp configuration, rottlerin (1 microM) decreased the firing of action potentials. I K(Ca) elicited by simulated action potential waveforms was enhanced by this compound. In human cortical HCN-1A cells, rottlerin (1 microM) could also interact with the BK(Ca) channel to stimulate I K(Ca). Therefore, rottlerin may directly activate BK(Ca) channels in neurons or endocrine cells.

Acetophenones↗
PubMed1994

Effects of phospholipase A2 inhibitors on the antidepressant-induced axonal regeneration of noradrenergic locus coeruleus neurons.

In previous experiments, we have shown that antidepressants such as desipramine (DMI) can induce axonal regeneration of noradrenergic locus coeruleus neurons. In this article, we suggest that phospholipase A2 is involved in the molecular mechanism of the antidepressant-induced regeneration of brain noradrenergic axons. The effects of the PLA2 inhibitors, mepacrine (MEP) or 4-bromphenacyl bromide (BPB), upon the DMI-induced regeneration of noradrenergic axons in the rat cerebral cortex were assessed by either histofluorescence or immunohistochemistry using an antibody to dopamine-beta-hydroxylase. Symmetrical sites of the frontal cortex in both hemispheres were pretreated with 6-hydroxydopamine (6-OHDA). Then, the same cortical site of one hemisphere was infused with DMI by means of osmotic minipumps for more than 2 weeks, while the corresponding cortical site of the other hemisphere was infused with DMI plus MEP or BPB. It was found that the PLA2 inhibitors could attenuate the DMI-induced regeneration of noradrenergic axons. Thus, if axonal retraction or degeneration of brain noradrenergic neurons is involved in the pathogenesis of clinical depression, elucidating the malfunction of the PLA2 systems may provide substantial evidence to aid in our understanding of the cause of depression at the molecular level.

Acetophenones↗
PubMed2004

The switch mechanism of the cell death mode from apoptosis to necrosis in menadione-treated human osteosarcoma cell line 143B cells.

Time-dependent changes in the cell death mode from apoptosis to necrosis were studied in cultured 143B cells treated with menadione, an anti-cancerous drug, excluding a possible involvement of "secondary necrosis." The population of apoptotic cells judged by FITC-Annexin V and propidium iodide (PI) double staining reached its maximum at 6 hours after 100 microM menadione treatment followed by an abrupt decrease thereafter, while that of necrotic cells continuously increased reaching 90% at 24 hours. Electron microscopically, cells attached to the culture dish at 6 hours after the treatment consisted of two different types of cells: cells with typical apoptotic features occupying the major population and those with condensed nuclei and swollen cytoplasm. Cells attached to the culture dish at 8 hours after the treatment consisted exclusively of those with condensed nuclei and swollen cytoplasm. Mitochondria in these cells showed various structural changes: those swollen to various degrees with deposition of flocculent densities, or those with highly condensed matrix. Distinct decreases both in intracellular levels of ATP and caspase-3-like activities and remarkable elevations of intracellular levels of superoxide, which were partly suppressed by NAD(P)H oxidase inhibitors, occurred at 6 hours after the treatment. These results may suggest that distinct increases of the intracellular level of superoxide derived from plasma membrane NAD(P)H oxidase besides that from mitochondria have triggered the transition of cell death mode from apoptosis to necrosis. Transition of highly condensed mitochondria to extremely swollen ones may reflect necrotic processes in menadione-treated cells. The present study strongly suggests that time-dependent study is essential using the electron microscopic technique to analyze detailed processes in the changes of the cell death mode.

Acetophenones↗
PubMed2006

Effect of protein kinase C inhibitors on porcine oocyte activation.

The effect of protein kinase C (PKC) inhibitors on porcine oocyte activation by calcium ionophore A23187 was studied. Calcium ionophore applied in a 50 microM concentration for 10 min induced activation in 74% of oocytes matured in vitro. When the ionophore-treated oocytes were exposed to the effect of bisindolylmaleimide I, which inhibits calcium-dependent PKC isotypes (PKC-alpha, -beta(I), -beta(II), -gamma,) and calcium-independent PKC isotypes (PKC-delta, -epsilon), the portion of activated oocytes decreased (at a concentration of 100 nM, 2% of the oocytes were activated). Go6976, the inhibitor of calcium-dependent PKC isotypes PKC-alpha, -beta(I) did not prevent the action of the oocytes treated with calcium ionophore in concentrations from 1 to 100 microM. The inhibitor of PKC-beta(I) and beta(II) isotypes, hispidin, in a concentration of 2 microM-2 mM, was not effective either. The inhibitor of PKC-delta isotype, rottlerin, suppressed activation of the oocytes by calcium ionophore (no oocyte was activated at 10 microM concentration). The PKC-delta isotype in matured porcine oocytes, studied by Western blot analysis, appeared as non-truncated PKC-delta of 77.5 kDa molecular weight, on the one hand, and as truncated PKC-delta, which was present in the form of a doublet of approximately 62.5 and 68 kDa molecular weight, on the other hand. On the basis of these results, it can be supposed that PKC participates in the regulation of processes associated with oocyte activation. Calcium-dependent PKC-alpha, -beta isotypes do not seem to play any significant role in calcium activation. The activation seems to depend on the activity of the calcium-independent PKC-delta isoform.

Acetophenones↗
PubMed1996

Human type II phospholipase A2-induced Mac-1 expression on human neutrophils.

To investigate the effect of type II phospholipase A2 (PLA2-II) on neutrophil function, we assessed the Mac-1 (CD11b/CD18) expression on human neutrophils by flow cytometry after incubation of the cells with human PLA2-II. PLA2-II at a concentration of 10 microg/mL increased the Mac-1 expression by 150% compared with unstimulated cells at 30 min and after. Under these conditions PLA2-II increased the exocytosis from secretory vesicles but not from azurophilic, specific, or gelatinase granules. The results suggest that PLA2-II induces translocation of Mac-1 from the secretory vesicles to the plasma membrane. The Mac-1 induction mediated by PLA2-II was inhibited by an anti-PLA2-II antibody, which was able to inhibit the catalytic activity. However, the Mac-1 induction by PLA2-II was not inhibited by a 5-lipoxygenase, cyclooxygenase inhibitor, or a platelet-activating factor antagonist. Thus, we examined the effects of fatty acids and lysophospholipids on Mac-1 expression. Only arachidonic acid induced Mac-1 expression. These results imply that PLA2-II induces Mac-1 expression on neutrophils via production of arachidonic acid.

Acetophenones↗
PubMed2000

Rottlerin, a PKC isozyme-selective inhibitor, affects signaling events and cytokine production in human monocytes.

The implication of select protein kinase C (PKC) isoenzymes in cytokine production by human monocytes was investigated using an isozyme-selective inhibitor of PKC, rottlerin. We found that lipopolysaccharide (LPS) triggers cytosol-to-membrane translocation of PKCalpha and delta isoenzymes, whereas phorbol ester (PMA) induces translocation of several PKC isoforms. Moreover, we show that in LPS- and PMA-stimulated monocytes rottlerin affects several cellular responses. (1) At low (15 microM) concentration it blocks translocation of PKCdelta, diminishes DNA binding activity of AP-1 transcription factor, and attenuates cytokine production [tumor necrosis factor alpha (TNF-alpha) > interleukin-1beta (IL-1beta)]. (2) At high (50 microM) concentration it prevents translocation of PKCalpha, and subsequently inhibits ERK1/ERK2 phosphorylation, DNA binding activities of AP-1 and nuclear factor-KB transcription factors, and the production of both tested cytokines. Thus, we propose that cytosol-to-membrane translocation of PKCalpha and PKdelta isoenzymes may represent early steps in the signaling cascades that lead to TNF-alpha and IL-1beta production in human monocytes.

Acetophenones↗
PubMed2000

Effects of selective protein kinase C inhibitors on the proteolytic down-regulation of L-selectin from chemoattractant-activated neutrophils.

The signaling factors that direct the rapid shedding of L-selectin from neutrophils upon chemoattractant stimulation are poorly understood. Protein kinase C (PKC) has been implicated, yet previous studies have relied on the use of phorbol esters and nonselective kinase inhibitors. We treated neutrophils with various selective kinase inhibitors to evaluate their effects on N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced L-selectin shedding. We found that three selective inhibitors of PKC, structurally related to staurosporine, largely blocked both fMLP- and phorbol 12-myristate 13-acetate (PMA)-induced L-selectin shedding; however, these inhibitors did not affect fMLP-induced up-regulation of Mac-1 (CD11b/CD18) expression, which has been shown not to involve PKC. Other selective serine, threonine, and tyrosine kinase inhibitors were found not to block fMLP-induced L-selectin shedding. These findings provide more definitive evidence for the role of PKC in chemoattractant-induced L-selectin proteolysis. It is interesting that certain highly selective PKC inhibitors, not structurally related to staurosporine, were found to directly induce L-selectin shedding from neutrophils.

Acetophenones↗
PubMed2004

Amino- and carboxyl-terminal mutants of presenilin 1 cause neuronal cell death through distinct toxic mechanisms: Study of 27 different presenilin 1 mutants.

Presenilin (PS)1 and its mutants, which consist of the N-terminal and C-terminal fragments, cause certain familial forms of Alzheimer's disease (FAD). Our earlier studies found that FAD-linked M146L-PS1 causes neuronal cell death through nitrogen oxide synthase (NOS) and that FAD-linked N141I-PS2, another member of the PS family, causes neuronal cell death through NADPH oxidase. In this study, we examined 27 different FAD-linked mutants of PS1, and found that PS1 mutants with mutations in the N-terminal fragment caused NOS inhibitor (NOSI)-sensitive neuronal cell death; in contrast, the PS1 mutants with mutations in the C-terminal fragment caused NOSI-resistant neuronal cell death. The former toxicity was resistant to the specific NADPH oxidase inhibitor apocynin and was inhibited by Humanin (HN), a newly identified neuroprotective factor against Alzheimer's disease (AD)-relevant insults, but not by insulin-like growth factor-I (IGF-I). In contrast, the latter toxicity was sensitive to apocynin and inhibited by both IGF-I and HN. This study indicates for the first time that N- and C-terminal fragment PS1 mutants can generate distinct neurotoxic signals, which will provide an important clue to the understanding of the entire array of neurotoxic signals generated by FAD-causative mutations of PS1.

Acetophenones↗