ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen

Autor: Christian Pinna, Paolo Ciana, Electra Brunialti, G. E. Rovati, Giuseppe Battaglia, Massimo Locati, Chiara Sfogliarini, Elisabetta Vegeto, Giovanna Pepe, Adriana Maggi, Loris Rizzello, Federica Mornata
Rok vydání: 2021
Předmět:
Lipopolysaccharides
Selective Estrogen Receptor Modulators
Macròfags
medicine.drug_class
NF-E2-Related Factor 2
Inflammation
Apoptosis
macrophage
RM1-950
Biology
Nrf2
Proinflammatory cytokine
Càncer de mama
Receptors
G-Protein-Coupled
Immunomodulating Agents
Immune system
Breast cancer
Phagocytosis
medicine
Animals
Cells
Cultured
Pharmacology
Mice
Knockout
Innate immune system
drug repurposing
Macrophages
Estrogen Receptor alpha
Apoptosi
General Medicine
Mice
Inbred C57BL
Tamoxifen
Phenotype
Receptors
Estrogen
inflammation
Selective estrogen receptor modulator
Estrogen
Cancer research
Macrophages
Peritoneal
Tumor necrosis factor alpha
Female
Therapeutics. Pharmacology
medicine.symptom
Inflammation Mediators
hormones
hormone substitutes
and hormone antagonists
medicine.drug
Signal Transduction
Zdroj: Dipòsit Digital de la UB
Universidad de Barcelona
Biomedicine & Pharmacotherapy, Vol 144, Iss, Pp 112274-(2021)
Biomedicine & Pharmacotherapy
ISSN: 1950-6007
Popis: 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.
Databáze: OpenAIRE
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