Melatonin antagonizes apoptosis via receptor interaction in U937 monocytic cells

Abstract

Among the non-neurological functions of melatonin, much attention is being directed to the ability of melatonin to modulate the immune system, whose cells possess melatonin-specific receptors and biosynthetic enzymes. Melatonin controls cell behaviour by eliciting specific signal transduction actions after its interaction with plasma membrane receptors (MT(1), MT(2)); additionally, melatonin potently neutralizes free radicals. Melatonin regulates immune cell loss by antagonizing apoptosis. A major unsolved question is whether this is due to receptor involvement, or to radical scavenging considering that apoptosis is often dependent on oxidative alterations. Here, we provide evidence that on U937 monocytic cells, apoptosis is antagonized by melatonin by receptor interaction rather than by radical scavenging. First, melatonin and a set of synthetic analogues prevented apoptosis in a manner that is proportional to their affinity for plasma membrane receptors but not to their antioxidant ability. Secondly, melatonin's antiapoptotic effect required key signal transduction events including G protein, phospholipase C and Ca(2+) influx and, more important, it is sensitive to the specific melatonin receptor antagonist luzindole.

Melatonin: A pleiotropic molecule regulating inflammation

“…Studies in peripheral blood have suggested that melatonin inhibits apoptotic processes via its antioxidant properties [106], which is in line with many evidences showing that in some instances the apoptotic process occurs via oxidative signaling [107]. Alternative mechanisms have been proposed; in U937 monocytes, melatonin reduces apoptosis via intracellular signal transduction stimulated by interaction with MT1/MT2 plasma membrane receptors [23]. However, the majority of reports indicate that the anti-apoptotic of melatonin occurs by acting on the abundance of the two main members of the Bcl-2 family, namely the pro-apoptotic Bax and the anti-apoptotic Bcl-2 proteins [108].…”

“…Indeed, melatonin inhibits apoptosis of precursor B cells in mouse bone marrow [105]. Moreover, an anti-apoptotic effect on different leukocytes was also demonstrated [23,102].…”

“…Even though the mechanisms through which melatonin stimulates these signal transduction pathways have been extensively studied [12][13][14][15][16][17][18][19][20][21], little is known about the resulting cellular effects: MT1/MT2 receptors have been shown to mediate melatonin-dependent decrease of tumor cell proliferation [22] and anti-apoptotic effects [23][24][25]; MT1 seems to be responsible for the general response to photoperiodic signals [26].…”

“…In addition, it was demonstrated that pharmacological doses of melatonin inhibit INF- production in a range of 0.1 to 1mM [65]. In some systems, the modulation of apoptosis requires high melatonin doses [23,24].…”

Melatonin controls oxidative stress and modulates iron, ferritin, and transferrin levels in adriamycin treated rats

“…Therefore, suitable chelators may prevent ADR-mediated cytotoxicity and potentiate its antitumor activity. MLT binds iron (Limson et al, 1998;Maharaj et al, 2003), exerts remarkable oncostatic and antiproliferative effects on different kinds of tumors (El-Missiry and Abd El-Aziz, 2000;Cos and SanchezBarcelo, 1995) and antagonizes apoptosis (Radogna et al, 2007). Thus, MLT might have dual actions; control ADR-mediated disturbance of iron homeostasis and decreasing oncogenesis.…”