ISSN: 2161-1017
+44 1478 350008
Mirco Masi, Buoso Erica, Valentina Galbiati, Ambra Maddalon, Martina Iulini, Marina Marinovich, Marco Racchi, Emanuela Corsini
Dipartimento di Scienze del Farmaco, Università Degli Studi di Pavia, Viale Taramelli 12/14, 27100, Pavia, Italy.
Scuola Universitaria Superiore IUSS, Piazza della Vittoria 15, 27100, Pavia, Italy.
Laboratory of Toxicology, Dipartimento di Scienze Politiche ed Ambientali, Università Degli Studi di Milano, Via Balzaretti 9, 20133, Milano, Italy.
Laboratory of Toxicology, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università Degli Studi di Milano, Via Balzaretti 9, 20133, Milano, Italy.
Scientific Tracks Abstracts: EMS
Background: Cancers, autoimmune diseases and allergies arose in most industrialized countries, and a role of endocrine disrupting chemicals (EDCs) has been hypothesized. EDCs have been linked with immune alterations due to inflammation-enhancing and immunosuppressive properties. Therefore, elucidating how EDCs interfere with the immune response is becoming of pivotal interest. Since we demonstrated a tight correlation between RACK1 expression and immune cells activation via PKC, RACK1 was investigated as an EDC target. Indeed, a hormone-related regulatory element for glucocorticoids and androgens was found in rack1 gene promoter to mediate its transcriptional regulation, resulting in modulation of cytokine production. Methods: To investigate EDCs ability to modulate RACK1 expression, human promyelocytic THP1 cells were treated with increasing concentrations of p,p’DDT (weak AR antagonist), p,p’DDE (strong AR antagonist), nandrolone (AR agonist), estrogen-active compounds 17β-estradiol, 17β-estradiol-BSA, diethylstilbestrol (DES), zearalenone (ZEA), flutamide and agonist G1. Luciferase reporter assay, qPCR, Western blot analysis and specific sandwich ELISA and flow cytometric analysis were performed. Results: p,p′DDT and p,p′DDE induced a significant decrease in RACK1 transcriptional activity, RACK1 expression, LPS-induced IL-8 and TNF-α production and CD86 expression. Consistent with its stronger AR antagonistic effect, p,p′DDE exerts a stronger repressor effect than p,p′DDT. On the other hand, 17β-estradiol, DES, and ZEA (through GPER activation) increased RACK1 transcriptional activity and its expression, which paralleled an increase in LPS-induced IL-8, TNF-α production, and CD86 expression all dependent on RACK1/PKCβII activation. Flutamide completely prevented DES-induced RACK1 transcriptional activity and protein expression, confirming a role for AR in RACK1 transcription regulation. Conclusions: A complex effect results from the activity as agonist or antagonist of estrogens, androgens or glucocorticoids indicating that RACK1 could be a relevant target of steroid-active compounds and EDCs. Hence, RACK1 represents a bridge between the endocrine system and the innate immune system, offering the opportunity to use RACK1 as a possible screening tool for immunotoxic potential of hormone-active substances.
Mirco Masi is a PhD student at University School for Advanced Studies IUSS in Pavia. He is currently working on a project that aims to understand the involvement of scaffold and ribosomal protein RACK1 (Receptor for Activated C Kinase 1) in breast cancer migration and proliferation. As a collaborator, he joined an international project to study RACK1 role in immune system activation and cytokines release via PKCβII in toxicology context, with a specific focus on the effects of different types of Endocrine Disrupting Chemicals (EDCs) on RACK1 expression and their immunologic implications.