Melatonin Inhibits Glucocorticoid Receptor Nuclear Translocation in Mouse Thymocytes

Abstract

The antiapoptotic effect of melatonin (MEL) has been described in several systems. In particular, MEL inhibits glucocorticoid-mediated apoptosis. Our group previously demonstrated that in the thymus, MEL inhibits the release of Cytochrome C from mitochondria and the dexamethasone-dependent increase of bax mRNA levels. In this study we analyzed the ability of MEL to regulate the activation of the glucocorticoid receptor (GR) in mouse thymocytes. We found that even though the methoxyindole does not affect the ligand binding capacity of the receptor, it impairs the steroid-dependent nuclear translocation of the GR and also prevents transformation by blocking the dissociation of the 90-kDa heat shock protein. Coincubation of the methoxyindole with dexamethasone did not affect the expression of a reporter gene in GR-transfected Cos-7 cells or HC11 and L929 mouse cell lines that express Mel-1a and retinoid-related orphan receptor-alpha (RORalpha) receptors. Therefore, the antagonistic effect of MEL seems to be specific for thymocytes, in a Mel 1a- and RORalpha-independent manner. In summary, the present results suggest a novel mechanism for the antagonistic action of MEL on GR-mediated effects, which involves the inhibition of 90-kDa heat shock protein dissociation and the cytoplasmic retention of the GR.

Melatonin biosynthesis in the thymus of humans and rats

“…The mechanisms whereby melatonin influences apoptosis have not yet been clarified, although different options have been suggested. Melatonin has been found to inhibit glucocorticoidand hydroxyl radical-induced thymocytes apoptosis, through its anti-oxidative effects and inhibiting glucocorticoid receptor nuclear translocation in thymocytes [41,66,67]. On the other hand, this molecule can protect the thymus by modulating zinc levels [68 -70], necessary for the active form of thymulin and other functions [71], and by increasing some thymic peptides production [42].…”

Melatonin prevents glucocorticoid inhibition of cell proliferation and toxicity in hippocampal cells by reducing glucocorticoid receptor nuclear translocation

“…Recent publications proposed that melatonin prevents GR nuclear translocation in a tissue specific dependent manner after glucocorticoid treatment [27]; however, its role on hippocampal cells is currently unknown. We studied the ability of melatonin to prevent GR nuclear translocation induced by DEX.…”

“…These actions are mediated by reductions in mRNA levels for GR in these cells [26]. More recently, it was found that even though melatonin does not affect protein levels or the binding activity of GR, it reduces its nuclear translocation by blocking its dissociation from the heat shock protein (Hsp90) in thymocytes [27].…”

A role for melatonin in maintaining the pro- and anti-inflammatory balance by influencing leukocyte migration and apoptosis in carp

“…In contrast, several studies report an antiapoptotic effect of melatonin. This anti-apoptotic effect may be associated to its antioxidative action (Sainz et al, 1999;Espino et al, 2011), to its inhibition of the nuclear translocation of glucocorticoid receptors (Sainz et al, 1999;Presman et al, 2006), to its modification of zinc levels (Mocchegiani et al, 1994) or to up-and downregulation of gene expression of Bcl-2 and Bax protein respectively (Jing et al, 2014). Espino et al (2010) moreover found that in human neutrophils melatonin inhibited apoptosis via reduction of caspase-9 and -3 activity as well as through reduction of the mitochondrial permeability to ions (Espino et al, 2010).…”