title: Role of androgens in dhea-induced rack1 expression and cytokine modulation in monocytes.
abstract: BACKGROUND
  Over the past fifteen years, we have demonstrated that cortisol and dehydroepiandrosterone (DHEA) have opposite effects on the regulation of protein kinase C (PKC) activity in the context of the immune system. The anti-glucocorticoid effect of DHEA is also related to the regulation of splicing of the glucocorticoid receptor (GR), promoting the expression of GRβ isoform, which acts as a negative dominant form on GRα activity. Moreover, it is very well known that DHEA can be metabolized to androgens like testosterone, dihydrotestosterone (DHT), and its metabolites 3α-diol and 3β-diol, which exert their function through the binding of the androgen receptor (AR). Based on this knowledge, and on early observation that castrated animals show results similar to those observed in old animals, the purpose of this study is to investigate the role of androgens and the androgen receptor (AR) in DHEA-induced expression of the PKC signaling molecule RACK1 (Receptor for Activated C Kinase 1) and cytokine production in monocytes.
  
  
  RESULTS
  Here we demonstrated the ability of the anti-androgen molecule, flutamide, to counteract the stimulatory effects of DHEA on RACK1 and GRβ expression, and cytokine production. In both THP-1 cells and human peripheral blood mononuclear cells (PBMC), flutamide blocked the effects of DHEA, suggesting a role of the AR in these effects. As DHEA is not considered a direct AR agonist, we investigated the metabolism of DHEA in THP-1 cells. We evaluated the ability of testosterone, DHT, and androstenedione to induce RACK1 expression and cytokine production. In analogy to DHEA, an increase in RACK1 expression and in LPS-induced IL-8 and TNF-α production was observed after treatment with these selected androgens. Finally, the silencing of AR with siRNA completely prevented DHEA-induced RACK1 mRNA expression, supporting the idea that AR is involved in DHEA effects.
  
  
  CONCLUSIONS
  We demonstrated that the conversion of DHEA to active androgens, which act via AR, is a key mechanism in the effect of DHEA on RACK1 expression and monocyte activation. This data supports the existence of a complex hormonal balance in the control of immune modulation, which can be further studied in the context of immunosenescence and endocrinosenescence.
authors.affiliation: Laboratory of Toxicology, Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, Milan, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Corsini
authors.affiliation: Laboratory of Toxicology, Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Galbiati
authors.affiliation: Laboratory of Toxicology, Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Papale
authors.affiliation: Laboratory of Toxicology, Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Kummer
authors.affiliation: Department of Drug Sciences - Pharmacology Unit, University of Pavia, Viale Taramelli 14, Pavia, 27100 Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Department of Drug Sciences - Pharmacology Unit, University of Pavia, Viale Taramelli 14, Pavia, 27100 Italy.
authors.forename: Melania M
authors.initials: MM
authors.lastname: Serafini
authors.affiliation: "Golgi Cenci" Foundation, Abbiategrasso, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Guaita
authors.affiliation: Mass Spectrometry Laboratory "Giovanni Galli", DiSFeB, Università degli Studi di Milano, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Spezzano
authors.affiliation: Mass Spectrometry Laboratory "Giovanni Galli", DiSFeB, Università degli Studi di Milano, Milan, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Caruso
authors.affiliation: Laboratory of Toxicology, Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Marinovich
authors.affiliation: Department of Drug Sciences - Pharmacology Unit, University of Pavia, Viale Taramelli 14, Pavia, 27100 Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Racchi
keywords: Androgens; Cytokines; Immunosenescence; Monocytes; PKC; Signal transduction