The sulfhydryl reagent thimerosal elicits human platelet aggregation by mobilization of intracellular calcium and secondary prostaglandin endoperoxide formation

Hecker, Markus; Brüne, Bernhard; Decker, Katja; Ullrich, Volker

doi:10.1016/0006-291x(89)92202-x

Cited by 53 publications

(21 citation statements)

References 17 publications

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“…inhibiting reacylation of AA into cellular phospholipids (33). Hecker et al (39) speculated that thimerosal only slightly increased liberated AA and that its mechanism of action in increasing leukotriene biosynthesis in the neutrophil was the result of further activation of cPLA 2 ␣. Kaever et al (33) suggested that the increased production of PGE 2 in P388D1 cells was a consequence of interfering with the fatty acid deacylation-reacylation cycle that would result in elevated concentrations of AA.…”

Section: Table 3 Effect Of Thimerosal On Lat Activity In Neutrophil Mmentioning

confidence: 99%

Effect of Arachidonic Acid Reacylation on Leukotriene Biosynthesis in Human Neutrophils Stimulated with Granulocyte-macrophage Colony-stimulating Factor and Formyl-methionyl-leucyl-phenylalanine

Zarini

Gijón

Folco

et al. 2006

Journal of Biological Chemistry

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Priming of human neutrophils with granulocyte-macrophage colony-stimulating factor (GM-CSF) followed by treatment with formyl-methionyl-leucyl-phenylalanine (fMLP) stimulates cells in a physiologically relevant manner with modest 5-lipoxygenase activation and formation of leukotrienes. However, pretreatment of neutrophils with thimerosal, an organomercury thiosalicylic acid derivative, led to a dramatic increase (>50-fold) in the production of leukotriene B 4 and 5-hydroxyeicosatetraenoic acid, significantly higher than that observed after stimulation with calcium ionophore A23187. Little or no effect was observed with thimerosal alone or in combination with either GM-CSF or fMLP. Elevation of [Ca 2؉ ] i induced by thimerosal in neutrophils stimulated with GM-CSF/ fMLP was similar but more sustained compared with samples where thimerosal was absent. However, [Ca 2؉ ] i was significantly lower compared with calcium ionophore-treated cells, suggesting that a sustained calcium rise was necessary but not sufficient to explain the effects of this compound on the GM-CSF/fMLP-stimulated neutrophil. Thimerosal was found to directly inhibit neutrophil lysophospholipid:acyl-CoA acyltransferase activity at the doses that stimulate leukotriene production, and analysis of lysates from neutrophil preparations stimulated in the presence of thimerosal showed a marked increase in free arachidonic acid, supporting the inhibition of the reincorporation of this fatty acid into the membrane phospholipids as a mechanism of action for this compound. The dramatic increase in production of leukotrienes by neutrophils when a physiological stimulus such as GM-CSF/fMLP is employed in the presence of thimerosal suggests a critical regulatory role of arachidonate reacylation that limits leukotriene biosynthesis in concert with 5-lipoxygenase and cytosolic phospholipase A 2 ␣ activation.Neutrophils play an important role in natural immunity and function to eliminate microbes and dead tissues. They are also a major cell involved in the acute inflammatory response, since they respond rapidly to chemotactic stimuli and can be activated by cytokines produced primarily by macrophages to perform degradative and phagocytic functions. Upon activation at the site of inflammation, they release lysosomal enzymes and neutral proteinases, reactive oxygen species, including H 2 O 2 and O 2 .(1, 2), and metabolites of arachidonic acid (AA), 2 in particular leukotriene B 4 (LTB 4 ) (3). Biosynthesis of leukotrienes involves the release of AA from membrane phospholipids by Ca 2ϩ -dependent cytosolic phospholipase A 2 ␣ (cPLA 2 ␣) (4) and its conversion into 5-hydroperoxyeicosatetraenoic acid and subsequently leukotriene A 4 (LTA 4 ), catalyzed by 5-lipoxygenase (5-LO) (5). LTA 4 is then enzymatically converted to LTB 4 by LTA 4 -hydrolase (6) or to leukotriene C 4 (LTC 4 ) by the addition of a molecule of glutathione through the action of LTC 4 -synthase (7). The site for most of these biochemical events is the perinuclear region (8).Regulation of leukotrie...

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Section: Table 3 Effect Of Thimerosal On Lat Activity In Neutrophil Mmentioning

confidence: 99%

Effect of Arachidonic Acid Reacylation on Leukotriene Biosynthesis in Human Neutrophils Stimulated with Granulocyte-macrophage Colony-stimulating Factor and Formyl-methionyl-leucyl-phenylalanine

Zarini

Gijón

Folco

et al. 2006

Journal of Biological Chemistry

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“…There is evidence that reagents which oxidize SH groups mobilize Ca 2+ thereby increasing [Ca2+]i on platelets, hepatocytes, oocytes and insulin-secreting cells [11,[27][28][29]. In mouse pancreatic acinar cells, thimerosal mobilised Ca 2+ from the InsP3-sensitive intracellular pool and caused repetitive Ca 2+ spikes [13].…”

Section: • 2+mentioning

confidence: 99%

Thimerosal modulates the agonist‐specific cytosolic Ca²⁺ oscillatory patterns in single pancreatic acinar cells of mouse

Takeo

Kamimura

et al. 1996

FEBS Letters

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Modulation of the agonist-specific cytosolic Ca 2+ o~cillatory pattern by thimerosal has been investigated in single pancreatic acinar cells using patch-clamp perforated whole-cell recording to measure the calcium-dependent chloride current (lcl(c~÷)). 1 gM thimerosal, which falls to evoke Ca 2+ oscillation alone, clearly changed the pattern of Ca 2+ oscillation from pulsatile spikes (evoked by low concentrations of activators) to sinusoidal or transient oscillations. The mimetic action of thimerosal was independent of extracellniar Ca 2+, was blocked by extracellular application of dithiothreitol or 10 mM caffeine, as well as by internal perfusion with heparin; but was unaffected by ruthenium red. We conclude that thimerosal modulates the agonist-specific cytosolic Ca 2+ oscillatory patterns mediated by sensitizing the InsP3-indnced Ca 2+ release.

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“…The incorporation of fatty acids into lysophospholipids could be prevented by the inhibition of reacylation via the acylCoA-synthetase and the lysophospholipid acyltransferase. It has been shown that not only organomercury compounds such as ethylmercurithiosalicylate (3,5,6), MeHgCl (4), and p-hydroxymercurisalicylat (9) affect these enzymes, but also organolead inhibits the reincorporation of exogenous arachidonic acid (7) (Figure 1). This may lead to the assumption that the stimulated activity of the PLA2 rises the amount of lyso paf as well as of arachidonic acid when cells were treated with the organometal compounds.…”

Section: Discussionmentioning

confidence: 99%

“…More and more investigations have shown that environmental toxicants as heavy metal compounds affect this sensitive mechanism within human blood platelets (1)(2)(3)(4), macrophages (5), granulocytes (6)(7)(8), as well as in fibroblasts (9). These xenobiotics enhance the deacylation either via the activation of phospholipase A2 (2,7,8) or the inhibition of fatty acid-CoA synthetase or lysophospholipid acyltransferase (4)(5)(6) lipid mediators.…”

Section: Introductionmentioning

confidence: 99%

Effects of organometals on cellular signaling. II. Inhibition of reincorporation of free arachidonic acid and influence on paf-acether synthesis by triethyllead.

Krug

Mattern

Bidault

et al. 1994

Environ Health Perspect

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Organometal compounds affect many enzymes, especially those containing SH-groups as acyl-and acetyltransferases involved in lysophospholipid reacylation. In HL-60 cells, organotin and -lead compounds stimulate phospholipase A2 activity, contributing thus to increase the level of lysophospholipids. In the present study, we have tested whether paf-acether (paf) biosynthesis was affected by treatment with triethyllead (Et3PbCI) in HL-60 cells. Et3PbCI inhibits the incorporation of exogenous arachidonic acid in the presence of high (1 50 pM) but not low concentrations (< 1 pM). High concentrations of the lead compound are unable to induce paf formation by itself, however, lower concentrations (< 10 pM) acted synergistically with TPA or fMLP to stimulate paf formation. Whereas unstimulated cells produced 0.4 pmole paf/2 x 106 cells, the stimulation with low fMLP (0.1 pM) resulted in the synthesis of 1.7 pmole and with low TPA (2 ng/ml) in 0.5 pmole paf. Preincubation of the cells with 10 pM Et3PbCI for 20 to 30 min increased the amount of paf formed by these cells to 3.3 pmole after treatment with 0.1 pM fMLP and 1.5 pmole after TPA. Furthermore, the results showed an inhibition of acetyltransferase (the key enzyme of paf synthesis) by the high and not by low concentrations of the lead compound. We conclude that low concentrations of Et3PbCI (< 10 pM) may act as a synergistic inducer of paf synthesis initiated via a receptor-coupled stimulation. -Environ Health Perspect 102(Suppl 3): 331-334 (1994).

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The sulfhydryl reagent thimerosal elicits human platelet aggregation by mobilization of intracellular calcium and secondary prostaglandin endoperoxide formation

Cited by 53 publications

References 17 publications

Effect of Arachidonic Acid Reacylation on Leukotriene Biosynthesis in Human Neutrophils Stimulated with Granulocyte-macrophage Colony-stimulating Factor and Formyl-methionyl-leucyl-phenylalanine

Effect of Arachidonic Acid Reacylation on Leukotriene Biosynthesis in Human Neutrophils Stimulated with Granulocyte-macrophage Colony-stimulating Factor and Formyl-methionyl-leucyl-phenylalanine

Thimerosal modulates the agonist‐specific cytosolic Ca²⁺ oscillatory patterns in single pancreatic acinar cells of mouse

Effects of organometals on cellular signaling. II. Inhibition of reincorporation of free arachidonic acid and influence on paf-acether synthesis by triethyllead.

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The sulfhydryl reagent thimerosal elicits human platelet aggregation by mobilization of intracellular calcium and secondary prostaglandin endoperoxide formation

Cited by 53 publications

References 17 publications

Effect of Arachidonic Acid Reacylation on Leukotriene Biosynthesis in Human Neutrophils Stimulated with Granulocyte-macrophage Colony-stimulating Factor and Formyl-methionyl-leucyl-phenylalanine

Effect of Arachidonic Acid Reacylation on Leukotriene Biosynthesis in Human Neutrophils Stimulated with Granulocyte-macrophage Colony-stimulating Factor and Formyl-methionyl-leucyl-phenylalanine

Thimerosal modulates the agonist‐specific cytosolic Ca2+ oscillatory patterns in single pancreatic acinar cells of mouse

Effects of organometals on cellular signaling. II. Inhibition of reincorporation of free arachidonic acid and influence on paf-acether synthesis by triethyllead.

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Thimerosal modulates the agonist‐specific cytosolic Ca²⁺ oscillatory patterns in single pancreatic acinar cells of mouse