Diacylglycerols and mezerein activate neutrophils by a phorbol myristate acetate‐like mechanism

Jt, O'Flaherty; Jd, Schmitt; Rl, Wykle; Jf, Redman; Ce, McCall

doi:10.1002/jcp.1041250204

Cited by 21 publications

(7 citation statements)

References 32 publications

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“…These observations can be interpreted to indicate that actin is involved in release reactions of both azurophilic and specific granules of neutrophils and agree with reports showing that cytochalasin B increased the release of these vesicle components in neutrophils (28,29). Interestingly, stimulation of secretion by PMA was also enhanced by botulinum C2 toxin.…”

Section: Discussionsupporting

confidence: 91%

Botulinum C2 toxin ADP-ribosylates actin and enhances O2- production and secretion but inhibits migration of activated human neutrophils.

Norgauer¹,

Kownatzki²,

Seifert³

et al. 1988

J. Clin. Invest.

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The binary botulinum C2 toxin ADP-ribosylated the actin of human neutrophils. Treatment of human neutrophils with botulinum C2 toxin for 45 min increased FMLP-stimulated superoxide anion (O°) production 1.5-5-fold, whereas only a minor fraction of the cellular actin pool (-20%) was ADP-ribosylated. Effects of botulinum C2 toxin depended on toxin concentrations, presence of both components of the toxin, and incubation time. Cytochalasin B similarly enhanced O2 production. The effects of botulinum C2 toxin and cytochalasin B were additive at submaximally, but not maximally effective concentrations and incubation time of either toxin. Botulinum C2 toxin also enhanced stimulation of O2 production by Con A and platelet-activating factor, but not by phorbol 12-myristate 13-acetate (PMA). Botulinum C2 toxin increased FMLP-induced release of N-acetyl-glucosaminidase by 100-250%; release of vitamin B12-binding protein induced by FMLP and PMA was enhanced by -150 and 50%, respectively. Botulinum C2 toxin blocked both random migration of neutrophils and migration induced by FMLP, complement C5a, leukotriene B4, and a novel monocyte-derived chemotactic agent. The data suggest that botulinum C2 toxin-catalyzed ADP-ribosylation of a minor actin pool has a pronounced effect on the activation of human neutrophils by various stimulants.

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Section: Discussionsupporting

confidence: 91%

Botulinum C2 toxin ADP-ribosylates actin and enhances O2- production and secretion but inhibits migration of activated human neutrophils.

Norgauer¹,

Kownatzki²,

Seifert³

et al. 1988

J. Clin. Invest.

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“…One is that the inhibition of cell movement is caused by (a) enhanced cellular adhesiveness or (b) increased cell-cell adherence or (c) aggregation of the neutrophils, the last of which is a well recognized response to low doses of PMA (<10 nM) or diacylglycerols (Gallin et al, 1978;Sha'afi et al, 1983;O'Flaherty et al, 1985). However, we did not observe cell aggregates microscopically, and peripheral neutrophils aggregate less readily than elicited neutrophils, even when stirred (Bray et al, 1980).…”

Section: Discussioncontrasting

confidence: 56%

Divergent effects of co‐carcinogenic phorbol esters and a synthetic diacylglycerol on human neutrophil chemokinesis and granular enzyme secretion

Nourshargh

Hoult

1987

British J Pharmacology

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The effects of two co‐carcinogenic phorbol esters (phorbol myristate acetate (PMA) and phorbol dibutyrate (PDBu)) and a synthetic diacylglycerol (OAG, 1‐oleoyl‐2‐acetyl‐glycerol), which all stimulate protein kinase C, were compared with two inactive phorbol compounds (4α‐phorbol and 4α‐phorbol didecanoate (4α‐PDD)) on three functional properties of stimulated human polymorphonuclear leukocytes (PMNs): release of granular enzymes lysozyme and β‐glucuronidase, chemokinesis, and changes in cytoplasmic free calcium [Ca2+]i. PMA, PDBu and the diacylglycerol, OAG, all caused a dose‐dependent and slow (max by 15 min) release of small amounts of lysozyme with much less β‐glucuronidase and no release of cytoplasmic lactate dehydrogenase. Release was unaffected by removal of extracellular Ca2+. PMA, PDBu and OAG inhibited random movement of the cells, did not cause chemokinesis and induced a slow reduction in the basal [Ca2+]i, as measured by the quin‐2 method. PMA, PDBu and OAG increased the capacity of five independently‐acting stimulants (N‐formyl‐Met‐Leu‐Phe, leukotriene B4, C5a des‐Arg, platelet activating factor and A23187) to cause release of lysozyme and β‐glucuronidase but strongly inhibited PMN chemokinesis induced by the same five agents and reduced the stimulant‐induced increases in [Ca2+]i. PMA was always more potent than PDBu and much more potent than OAG in eliciting these stimulatory or inhibitory effects on human PMNs. In all tests, 4α‐phorbol and 4α‐PDD were inactive. The results confirm that stimulation of the diacylglycerol/protein kinase C system in human PMN, either by active phorbol esters or the synthetic diacylglycerol, causes bidirectional effects on human PMN function. In particular, activation of the C‐kinase causes inhibition of stimulated neutrophil motility, whereas the secretory functions of the cells are enhanced.

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“…In fact, H-7 appeared to significantly enhance release of floglucuronidase in the presence of both GTP-7-S and Ca 2+ (Panel C). Similarly, mezerein (a protein kinase C agonist at high concentrations and antagonist at low concentrations) [23,45] had little or no effect on secretion from permeabilized cells in the inhibitory range (Fig. 5).…”

Section: Lack Of Inhibition By Pkc Antagonistsmentioning

confidence: 88%

“…The activated G-proteins can stimulate a polyphosphoinositide-depen-~'To whom correspondence should be addressed: Dr J. E. Smolen, M7510 MSRBI, Box0684, Division of Pediatric Hematology/Oncology, University of Michigan, Ann Arbor, MI 48109-0684, U.S.A. dent phospholipaseC [14], leading to the generation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerols [15][16][17][18][19]. IP 3 has been shown to liberate Ca 2+ from intracellular sources [20][21][22], while diacylglycerol has been shown to be an activator of protein kinase C [23]; both processes are felt to lead ultimately to neutrophil responses such as lysosomal enzyme release and superoxide anion generation.…”

Section: Introductionmentioning

confidence: 99%

Protein kinase C is not involved in secretion by permeabilized human neutrophils

Smolen

Stoehr

Bartone

1989

Cellular Signalling

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The generally accepted sequence of intracellular signal transduction involves: (1) cell surface receptor-ligand interactions; (2) activation of G-proteins; (3) activation of phospholipase C, leading to inositol phosphate (IP3), and diacylglycerol production; (4) parallel mobilization of intracellular Ca2+ by IP3, and; (5) activation of protein kinase C (PKC) by diacylglycerol and Ca2+, leading to; (6) cellular responses. Human neutrophils appear to utilize this cascade, at least in general, and some, but not all, elements of the intracellular signal cascade known to be operating in intact cells also function in permeabilized cell systems. We have previously shown that permeabilized neutrophils can be induced to secrete lysosomal enzymes in response to elevated levels of Ca2+ alone and this secretion can be synergistically enhanced by the presence of guanine nucleotides. We now show that Ca2+, in the presence and absence of guanine nucleotides, can stimulate the production of soluble inositol phosphates. Furthermore, neomycin, a putative inhibitor of phospholipase C, can block Ca2(+)-induced secretion. These data thus suggest a role for phospholipase C activity or its products in the transduction process. The next enzymatic activity 'downstream' is PKC. Consequently, we looked at the role Mg-ATP, one of the substrates of PKC, plays in degranulation by permeabilized neutrophils, We found no obligatory role for this nucleotide in the secretory process. We then looked at the activity of oleoyl-acetyl-glycerol (OAG), a synthetic diacylglycerol and PKC agonist, on degranulation. We found that OAG was largely additive with Ca2+. Another PKC agonist, phorbol myristate acetate (PMA), also did not display notable synergy. Finally, inhibitors of PKC activity were not capable of blocking secretion, either in the presence or absence of guanine nucleotides. Thus, while circumstantial evidence seems to point towards a requirement for phospholipase C activation and diacylglycerol production in secretion, we were unable to demonstrate the next putative step in signal transduction, namely activation of PKC.

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Diacylglycerols and mezerein activate neutrophils by a phorbol myristate acetate‐like mechanism

Cited by 21 publications

References 32 publications

Botulinum C2 toxin ADP-ribosylates actin and enhances O2- production and secretion but inhibits migration of activated human neutrophils.

Botulinum C2 toxin ADP-ribosylates actin and enhances O2- production and secretion but inhibits migration of activated human neutrophils.

Divergent effects of co‐carcinogenic phorbol esters and a synthetic diacylglycerol on human neutrophil chemokinesis and granular enzyme secretion

Protein kinase C is not involved in secretion by permeabilized human neutrophils

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