Hydrogen sulfide is a toxic metabolite released by several bacterial agents under anaerobic conditions. In the present paper, we investigated the effects of sulfide on polymorphonuclear cell (PMN) apoptosis, a mechanism suggested for limiting the toxic potential of neutrophils in inflammatory sites. We showed that 1 mM sulfide (concentration not conditioning PMN viability) is able to enhance the apoptotic fate of human granulocytes by increasing: i) the number of cells containing pyknotic nuclei, ii) the internucleosomal cleavage, and, iii) the intensity of tubulin immunofluorescence staining. The sulfide effect is partially prevented by ionomycin and this finding is consistent with the hypothesis of the inhibiting role played by high levels of cytosolic calcium in PMN apoptosis modulating.
SummaryRetinoids are known to modulate several functions of mononuclear phagocytes. We have studied the effect of retinyl acetate (RAc) and retinoic acid (RA) on the production of procoagulant activity (PCA) by human peripheral blood mononuclear cells stimulated with endotoxin (1 εg/ml, 4 or 20 h at 37°C). Both compounds caused a dose-dependent reduction in the expression of cell-associated PCA (from 86 to <10% of control in the range of concentration comprised between 0.1 and 100 εM). This effect was also observed when the cells were exposed to retinoids for 10 min and washed before challenge with endotoxin, indicating that it is rapid and irreversible. In contrast, incubation of RAc or RA for 3 h at 37° C with cells that have been already stimulated with endotoxin (20 h at 37° C) remained without influence on cell PCA. The inhibitory action of retinoids was also observed when monocyte-enriched (>85%) preparations or highly purified monocyte-derived macrophages (>99%) were used instead of whole mononuclear cells. BW755C, an inhibitor of cyclo-oxygenase and lipoxygenase, reversed the inhibitory effect of retinoids, whereas acetylsalycilic acid, an inhibitor of cyclo-oxygenase, was inactive, suggesting the involvement of a lipoxygenase product. The inhibition of monocyte/macrophage PCA production and the subsequent reduction of cell potential for fibrin deposition might represent one of the mechanisms whereby retinoids exert their antiinflammatory and immunomodulatory activities.
Retinoids exhibit a wide spectrum of activities, including antiinflammatory properties. We have investigated the effect of retinoic acid (RA) and retinyl acetate (RAc) on the production of reactive oxygen metabolites and the release of lysosomal enzymes by human polymorphonuclear leukocytes (PMN). Incubation of PMN with RAc or RA (1-100 microM) caused a dose-dependent inhibition (upto 90%) in O2- production and chemiluminescence induced by phorbol myristate acetate (PMA), N-formyl-methionyl-leucyl-phenylanaline (fMLP), opsonized zymosan or ionophore A23187. Both retinoids (1-100 microM) also inhibited, in a dose-dependent way, degranulation induced by fMLP (upto 85% at the highest concentration of RA). These inhibitory effects appear irreversible, since they persist after the drugs are removed and the cells washed before stimulation. Inhibitors of cyclo-oxygenase activity such as acetylsalicyclic acid and indomethacin did not influence the effects of RAc. In contrast, BW755, an inhibitor of both cyclooxygenase and lipoxygenase, reversed the inhibitory action of RAc, suggesting that the effect of retinoids occurs possibly through the mediation of lipoxygenase products. The modulation of PMN oxidative metabolism and degranulation might help explain the antiinflammatory properties of retinoids.
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