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Effect of estrogen-active compounds on the expression of RACK1 and immunological implications

  • Immunotoxicology
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Abstract

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.

Article Highlights

  1. 1.

    RACK1 expression is induced by estrogenic active compounds.

  2. 2.

    Increased RACK1 levels correlate with increased response to LPS.

  3. 3.

    RACK1 evaluation offers the opportunity to screen the immunotoxic potential of steroid hormone-active substances.

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Acknowledgements

Research has been supported by Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN2017, Project number 2017MLC3NF) to Emanuela Corsini. We thank Francesca Pasini for excellent technical assistance.

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Correspondence to Emanuela Corsini.

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Buoso, E., Masi, M., Galbiati, V. et al. Effect of estrogen-active compounds on the expression of RACK1 and immunological implications. Arch Toxicol 94, 2081–2095 (2020). https://doi.org/10.1007/s00204-020-02756-9

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  • DOI: https://doi.org/10.1007/s00204-020-02756-9

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