Serotonin acts as a radical scavenger and is oxidized to a dimer during the respiratory burst of human mononuclear and polymorphonuclear phagocytes*

Abstract

Isolated human mononuclear and polymorphonuclear phagocytes were stimulated in the presence and absence of serotonin (5-HT), the major secretory product of activated platelets, and the release of reactive oxygen metabolites during the respiratory burst was assessed by luminol-enhanced chemiluminescence. In the presence of 5-HT, a dose-dependent suppression of the chemiluminescence signal occurred, irrespective of the stimulus used to elicit the respiratory burst. A similar suppression of luminol-enhanced chemiluminescence was also seen in a radical generating cell free system. 5-HT was found to be oxidized by the reactive oxygen species released by stimulated phagocytes. This oxidation is prevented in the presence of other antioxidants. The major 5-HT oxidation product was isolated by gel chromatography and identified by mass-spectrometry as a 5-HT dimer, probably 5,5'-dihydroxy-4,4'-bitryptamine. It is concluded that the 5-HT released from activated thrombocytes at sites of inflammation and endothelial cell damage acts as a true scavenger of reactive oxygen species generated during the respiratory burst of stimulated phagocytes and may thus modulate various aspects of cell-mediated defence reactions.

Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice

“…Some groups propose direct effects of serotonin on neutrophils in oxidative burst whereas others attribute serotonininduced effects to the release of messengers from endothelial cells or to direct extracellular effects of serotonin. 29,30 Serotonin did not induce significant superoxide production in an investigation of human neutrophils, 31 but decreased the production of reactive oxygen species in other studies. 32 Recently, it was reported that serotonin inhibited the oxidative burst in total leukocyte preparations from human blood, but not in isolated neutrophils.…”

“…[29][30][31][32][33][34] To date, the existence or nonexistence of serotonergic components in neutrophils has not been established. Some groups propose direct effects of serotonin on neutrophils in oxidative burst whereas others attribute serotonininduced effects to the release of messengers from endothelial cells or to direct extracellular effects of serotonin.…”

Oxidative stress in phagocytes—“The enemy within”

“…Some other tryptophan-derived metabolites were also found to display potent antioxidative properties in vitro as well as in vivo (Christen et al, 1990;Huether et al, 1990;Jovanovic and Simic, 1985;Liu and Mori, 1993;Pieriefiche et al, 1993;Schuff-Werner et al, 1995). Serotonin (5-hydroxytryptamine, 5-HT) and melatonin (N-acetyl-5-methoxytryptamine, MLT) are well known as physiologically important neurotransmitters involved in fundamental biological functions such as circadian rhythm, sleep control, reproduction, control of blood pressure, and aging.…”

“…We proposed that serotonin may act as an important endogenous scavenger of ROS generated during the respiratory burst of PMN and monocytes protecting host tissue as well as the phagocyte itself from oxidative damage (Schuff-Werner et al, 1995;Schuff-Werner and Splettstoesser 1999). Numerous findings concerning the interaction of 5-HT with oxygen radicals are consistent with this hypothesis: Serotonin was shown to protect isolated DNA from lesions induced by UV light or gamma-irradiation (Ivanova and Fraikin, 1985); its synthesis is induced by UV-radiation in yeasts, rendering them more resistant to challenge with UV-light or gamma-irradiation ("photoprotection") (Fraikin et al, 1981).…”

“…Until now, the mechanisms involved in the radical scavenging properties of 5-HT are not well understood. Low concentrations of 5-HT seem to increase the oxidation of cysteine and other thiols by MPO (acting as a co-substrate) (Svensson, 1989), whereas serotonin itself can be oxidized by oxidases in the presence of hydrogen peroxide, yielding a dimer or melanin-like polymers (Schuff-Werner et al, 1995;Wrona and Dryhurst, 1987). Additionally, 5-HT is metabolized by further enzymatic systems like coeruloplasmin (Eriksen et al, 1960), cytochrome-oxidase (Weber and Horita, 1963), and IDO (Yoshida et al, 1979).…”