We previously demonstrated the existence of a balance among steroid hormones, i.e. glucocorticoids and androgens, in RACK1 (receptor for activated C kinase 1) expression and innate immunity activation, which may offer the opportunity to use RACK1 expression as marker to evaluate immunotoxicity of hormone-active substances. Because of the existence of close interconnections between the different steroid hormone receptors with overlapping ligand specificities and signaling pathways, in this study, we wanted to investigate a possible effect of estrogenic active compounds, namely 17β-estradiol, diethylstilbestrol, and zearalenone, on RACK-1 expression and innate immune responses using THP-1 cells as experimental model. All compounds increased RACK1 transcriptional activity as evaluated by reporter luciferase activity, mRNA expression as assessed by real time-PCR and protein expression by western blot analysis, which paralleled an increase in LPS-induced IL-8, TNF-α production, and CD86 expression, which we previously demonstrated to be dependent on RACK1/PKCβ activation. As the induction of RACK1 expression can be blocked by the antagonist G15, induced by the agonist G1 and by the non-cell permeable 17β-estradiol conjugated with BSA, a role of GPER (previously named GPR30) activation in estrogen-induced RACK1 expression could be demonstrated. In addition, a role of androgen receptor (AR) in RACK1 transcription was also demonstrated by the ability of flutamide, a nonsteroidal antiandrogen, to completely prevent diethylstilbestrol-induced RACK1 transcriptional activity and protein expression. Altogether, our data suggest that RACK1 may represent an interesting target of steroid-active compounds, and its evaluation may offer the opportunity to screen the immunotoxic potential of hormone-active substances.
Effect of estrogen-active compounds on the expression of RACK1 and immunological implications / E. Buoso, M. Masi, V. Galbiati, A. Maddalon, M. Iulini, M. Kenda, M. Sollner Dolenc, M. Marinovich, M. Racchi, E. Corsini. - In: ARCHIVES OF TOXICOLOGY. - ISSN 0340-5761. - 94:6(2020 Jun), pp. 2081-2095.
|Titolo:||Effect of estrogen-active compounds on the expression of RACK1 and immunological implications|
CORSINI, EMANUELA (Ultimo) (Corresponding)
|Parole Chiave:||Cytokines; Endocrine-disrupting chemicals; Estrogens; Hormones; Immune system; Signal transduction|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Progetto:||ENDOCRINE DISRUPTORS: INVESTIGATION OF THE EFFECTS ON THE IMMUNE AND NERVOUS SYSTEMS (EDoNIS)|
|Data di pubblicazione:||giu-2020|
|Data ahead of print / Data di stampa:||apr-2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1007/s00204-020-02756-9|
|Appare nelle tipologie:||01 - Articolo su periodico|