ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen

ABSTRACT: 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 s...

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Autores principales:	Giovanna Pepe, Chiara Sfogliarini, Loris Rizzello, Giuseppe Battaglia, Christian Pinna, Gianenrico Rovati, Paolo Ciana, Electra Brunialti, Federica Mornata, Adriana Maggi, Massimo Locati, Elisabetta Vegeto
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	tamoxifen macrophage inflammation drug repurposing Nrf2 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/a7edf7f586f44f0282507cf6c6d73aa5
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spelling	oai:doaj.org-article:a7edf7f586f44f0282507cf6c6d73aa52021-11-14T04:29:08ZERα-independent NRF2-mediated immunoregulatory activity of tamoxifen0753-332210.1016/j.biopha.2021.112274https://doaj.org/article/a7edf7f586f44f0282507cf6c6d73aa52021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221010581https://doaj.org/toc/0753-3322ABSTRACT: 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. Using primary cultures of female mouse macrophages, we analyzed the expression of immune mediators and activation of effector functions in competition experiments with SERMs and 17β-estradiol (E2) or the bacterial endotoxin LPS. 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 and IL1β, with an overall increase in cell inflammatory phenotype, further sustained by potentiation of IL1β secretion through caspase-1 activation.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.Giovanna PepeChiara SfogliariniLoris RizzelloGiuseppe BattagliaChristian PinnaGianenrico RovatiPaolo CianaElectra BrunialtiFederica MornataAdriana MaggiMassimo LocatiElisabetta VegetoElsevierarticletamoxifenmacrophageinflammationdrug repurposingNrf2Therapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 144, Iss , Pp 112274- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	tamoxifen macrophage inflammation drug repurposing Nrf2 Therapeutics. Pharmacology RM1-950
spellingShingle	tamoxifen macrophage inflammation drug repurposing Nrf2 Therapeutics. Pharmacology RM1-950 Giovanna Pepe Chiara Sfogliarini Loris Rizzello Giuseppe Battaglia Christian Pinna Gianenrico Rovati Paolo Ciana Electra Brunialti Federica Mornata Adriana Maggi Massimo Locati Elisabetta Vegeto ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen
description	ABSTRACT: 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. Using primary cultures of female mouse macrophages, we analyzed the expression of immune mediators and activation of effector functions in competition experiments with SERMs and 17β-estradiol (E2) or the bacterial endotoxin LPS. 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 and IL1β, with an overall increase in cell inflammatory phenotype, further sustained by potentiation of IL1β secretion through caspase-1 activation.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.
format	article
author	Giovanna Pepe Chiara Sfogliarini Loris Rizzello Giuseppe Battaglia Christian Pinna Gianenrico Rovati Paolo Ciana Electra Brunialti Federica Mornata Adriana Maggi Massimo Locati Elisabetta Vegeto
author_facet	Giovanna Pepe Chiara Sfogliarini Loris Rizzello Giuseppe Battaglia Christian Pinna Gianenrico Rovati Paolo Ciana Electra Brunialti Federica Mornata Adriana Maggi Massimo Locati Elisabetta Vegeto
author_sort	Giovanna Pepe
title	ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen
title_short	ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen
title_full	ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen
title_fullStr	ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen
title_full_unstemmed	ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen
title_sort	erα-independent nrf2-mediated immunoregulatory activity of tamoxifen
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/a7edf7f586f44f0282507cf6c6d73aa5
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ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen

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