ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen.
Biomed Pharmacother
; 144: 112274, 2021 Dec.
Article
en En
| MEDLINE
| ID: mdl-34653752
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 17ß-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 IL1ß, with an overall increase in cell inflammatory phenotype, further sustained by potentiation of IL1ß 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Tamoxifeno
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Macrófagos Peritoneales
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Moduladores Selectivos de los Receptores de Estrógeno
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Receptor alfa de Estrógeno
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Factor 2 Relacionado con NF-E2
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Agentes Inmunomoduladores
Límite:
Animals
Idioma:
En
Revista:
Biomed Pharmacother
Año:
2021
Tipo del documento:
Article
País de afiliación:
Italia