loading page

ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen
  • +8
  • Giovanna Pepe,
  • Chiara Sfogliarini,
  • Loris Rizzello,
  • Giuseppe Battaglia,
  • Christian Pinna,
  • Gianenrico Rovati,
  • Paolo Ciana,
  • Electra Brunilati,
  • Adriana Maggi,
  • Massimo Locati,
  • Elisabetta Vegeto
Giovanna Pepe
University of Milan
Author Profile
Chiara Sfogliarini
University of Milan
Author Profile
Loris Rizzello
University of Milan
Author Profile
Giuseppe Battaglia
University College London
Author Profile
Christian Pinna
University of Milan
Author Profile
Gianenrico Rovati
University of Milan
Author Profile
Paolo Ciana
University of Milan
Author Profile
Electra Brunilati
University of Milan
Author Profile
Adriana Maggi
University of Milan
Author Profile
Massimo Locati
University of Milan
Author Profile
Elisabetta Vegeto
University of Milan

Corresponding Author:elisabetta.vegeto@unimi.it

Author Profile

Abstract

Background and Purpose: Sex differences in immune-mediated diseases are linked to the activity of estrogens on innate immunity cells, including macrophages. Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in estrogen receptor-alpha (ERα)-dependent breast cancers and off-target indications such as infections, although the immune activity of TAM and its active metabolite, 4-OH tamoxifen (4HT), is poorly characterized. Here, we aimed at investigating the endocrine and immune activity of these SERMs in macrophages. Experimental Approach: Using primary cultures of female mouse macrophages, we analyzed the expression of immune mediators and activation of effectors functions in competition experiments with SERMS and 17β-estradiol (E2) or the bacterial endotoxin LPS. Key results: We observed that 4HT and TAM induce estrogen antagonist effects when used at nanomolar concentrations, while pharmacological concentrations that are reached by TAM in clinical settings regulate the expression of VEGFα and other immune activation genes by ERα- and G protein-coupled receptor 1 (GPER1)-independent mechanisms that involve NRF2 through PI3K/Akt-dependent mechanisms. Importantly, we observed that SERMs potentiate cell phagocytosis and modify the effects of LPS on the expression of inflammatory cytokines, such as TNFα, IL-6 and IL1-β, with an overall increase in cell inflammatory phenotype, further sustained by potentiation of IL1-β secretion through caspase-1 activation. Conclusion and Implications: Altogether, our data unravel a novel molecular mechanism and immune functions for TAM and 4HT, sustaining their repurposing in infective and other estrogen receptors-unrelated pathologies.