17β-estradiol inhibits Notch1 activation in murine macrophage cell line RAW 264.7.

Autor: Severi P; Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy., Ascierto A; Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy., Marracino L; Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy., Ouambo Talla AW; Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy., Aquila G; Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy., Martino V; Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy., Dalessandro F; Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy., Scarpante I; Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy., Minghini G; Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy., Haffreingue L; Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy., Vieceli Dalla Sega F; GVM Care & Research, Maria Cecilia Hospital, Cotignola, 48033, Italy., Fortini F; GVM Care & Research, Maria Cecilia Hospital, Cotignola, 48033, Italy., Rizzo P; Department of Translational Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, 44124, Italy. rzzpla@unife.it.; GVM Care & Research, Maria Cecilia Hospital, Cotignola, 48033, Italy. rzzpla@unife.it.
Jazyk: angličtina
Zdroj: Molecular biology reports [Mol Biol Rep] 2024 Nov 08; Vol. 51 (1), pp. 1134. Date of Electronic Publication: 2024 Nov 08.
DOI: 10.1007/s11033-024-10058-x
Abstrakt: Background: Macrophages are major effectors in regulating immune response and inflammation. The pro-inflammatory phenotype (M1) is induced by the activation of the Toll-like receptor 4 (TLR4) on the macrophage surface, which recognizes lipopolysaccharide (LPS), a component of Gram-negative bacterial wall, and by the binding of interferon-gamma (IFNγ), a cytokine released by activated T lymphocytes, to its receptor (IFNGR). Among the pathways activated by LPS/IFNγ is the Notch pathway, which promotes the M1 phenotype. Conversely, 17β-estradiol (E2) has been shown to blunt LPS-mediated inflammatory response. While it has been shown that E2 regulates the activity of the Notch1 receptor in human endothelial cells, there is no evidence of estrogen-mediated regulation of Notch1 in macrophages.
Methods and Results: In this study, RAW 264.7 cells were stimulated with LPS/IFNγ in the presence or absence of E2 and/or N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), an inhibitor of γ-secretase, the enzyme involved in Notch activation. The effects of treatment on inducible nitric oxide synthase (iNOS), on components of the Notch pathway, and MAPK (mitogen-activated protein kinase) were assessed by quantitative PCR and Western blotting. We found that E2, through a mechanism involving the inhibition of p38 phosphorylation, reduces the activation of Notch1 induced by LPS/IFNγ. On the contrary, Notch1 exerts a negative control on the estrogen receptor α (ERα) since Notch1 inhibition increases the protein levels of this receptor.
Conclusion: In conclusion, we report for the first time a Notch-ERα interaction in macrophages. Our data suggest that E2 may reduce LPS/IFNγ-mediated M1 pro-inflammatory phenotype in macrophages by inhibiting Notch1. This finding encourages further studies on Notch1 inhibitors as novel treatments for inflammation-related diseases.
(© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)
Databáze: MEDLINE
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