The immune activity of selective estrogen receptor modulators is gene and macrophage subtype-specific yet converges on Il1b downregulation.

Autor: Sfogliarini C; Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy. Electronic address: chiara.sfogliarini@unimi.it., Pepe G; Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy. Electronic address: giovanna.pepe@unimi.it., Cesta CM; Dompé Pharmaceutici S.p.A., 67100 L'Aquila, Italy. Electronic address: candida.cesta@dompe.com., Allegretti M; Dompé Pharmaceutici S.p.A., 67100 L'Aquila, Italy. Electronic address: marcello.allegretti@dompe.com., Locati M; IRCCS Humanitas Research Hospital, via Manzoni 56, Rozzano, 20089 Milan, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy. Electronic address: Massimo.Locati@humanitasresearch.it., Vegeto E; Department of Pharmaceutical Sciences, University of Milan, 20133 Milan, Italy. Electronic address: elisabetta.vegeto@unimi.it.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2023 Sep; Vol. 165, pp. 115008. Date of Electronic Publication: 2023 Jul 11.
DOI: 10.1016/j.biopha.2023.115008
Abstrakt: Raloxifene belongs to the family of Selective Estrogen Receptor Modulators (SERMs), which are drugs widely prescribed for Estrogen Receptor alpha (ERα)-related pathologies. Recently, SERMs are being tested in repurposing strategies for ERα-independent clinical indications, including a wide range of microbial infections. Macrophages are central in the fight against pathogen invasion. Despite estrogens have been shown to regulate macrophage phenotype, SERMs activity in these cells is still poorly defined. We investigated the activity of Raloxifene in comparison with another widely used SERM, Tamoxifen, on immune gene expression in macrophages obtained from mouse and human tissues, including mouse peritoneal macrophages, bone marrow-derived macrophages, microglia or human blood-derived macrophages, assaying for the involvement of the ERα, PI3K and NRF2 pathways also under inflammatory conditions. Our data demonstrate that Raloxifene acts by a dual mechanism, which entails ERα antagonism and off-target mediators. Moreover, micromolar concentrations of Raloxifene increase the expression of immune metabolic genes, such as Vegfa and Hmox1, through PI3K and NRF2 activation selectively in peritoneal macrophages. Conversely, Il1b mRNA down-regulation by SERMs is consistently observed in all macrophage subtypes and unrelated to the PI3K/NRF2 system. Importantly, the production of the inflammatory cytokine TNFα induced by the bacterial endotoxin, LPS, is potentiated by SERMs and paralleled by the cell subtype-specific increase in IL1β secretion. This work extends our knowledge on the biological and molecular mechanisms of SERMs immune activity and indicate macrophages as a pharmacological target for the exploitation of the antimicrobial potential of these drugs.
Competing Interests: Declaration of Competing Interest The authors declare that are no conflicts of interest.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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