Pepe, G;
Sfogliarini, C;
Rizzello, L;
Battaglia, G;
Pinna, C;
Rovati, G;
Ciana, P;
... Vegeto, E; + view all
(2021)
ER alpha-independent NRF2-mediated immunoregulatory activity of tamoxifen.
Biomedicine & Pharmacotherapy
, 144
, Article 112274. 10.1016/j.biopha.2021.112274.
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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.
| Type: | Article |
|---|---|
| Title: | ER alpha-independent NRF2-mediated immunoregulatory activity of tamoxifen |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.biopha.2021.112274 |
| Publisher version: | https://doi.org/10.1016/j.biopha.2021.112274 |
| Language: | English |
| Additional information: | This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Medicine, Research & Experimental, Pharmacology & Pharmacy, Research & Experimental Medicine, tamoxifen, macrophage, inflammation, drug repurposing, Nrf2, TUMOR-ASSOCIATED MACROPHAGES, BREAST-CANCER, SEX-DIFFERENCES, RESISTANCE, EXPRESSION, APOPTOSIS, NRF2 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10139475 |
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