Estradiol inhibits differentiation of mouse macrophage into a pro-inflammatory phenotype by upregulating the IRE1α-XBP1 signaling axis.
10.12122/j.issn.1673-4254.2022.03.17
- Author:
Ling Jian ZHUO
1
;
Shuo Chen WANG
1
;
Xing LIU
1
;
Bao An CHEN
1
;
Xiang LI
1
Author Information
1. Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
- Publication Type:Journal Article
- Keywords:
endoplasmic reticulum stress pathway;
estrogen;
macrophages
- MeSH:
Animals;
Cell Differentiation/drug effects*;
Endoribonucleases/metabolism*;
Estradiol/pharmacology*;
Estrogens/metabolism*;
Interleukin-10;
Interleukin-6/metabolism*;
Macrophages, Peritoneal/metabolism*;
Mice;
Phenotype;
Protein Serine-Threonine Kinases/metabolism*;
RNA, Messenger/metabolism*;
Signal Transduction/drug effects*;
Transforming Growth Factor beta/metabolism*;
Tumor Necrosis Factor-alpha/metabolism*;
Up-Regulation/drug effects*;
X-Box Binding Protein 1/metabolism*
- From:
Journal of Southern Medical University
2022;42(3):432-437
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To explore the mechanism by which estradiol modulates the immunophenotype of macrophages through the endoplasmic reticulum stress pathway.
METHODS:Peritoneal macrophages isolated from C57 mice were cultured in the presence of 60 ng/mL interferon-γ (IFN-γ) followed by treatment with estradiol (1.0 nmol/L) alone, estradiol with estrogen receptor antagonist (Acolbifene, 4 nmol/L), estradiol with IRE1α inhibitor (4 μ 8 C), or estradiol with IRE1α agonist. After the treatments, the expression levels of MHC-Ⅱ, iNOS and endoplasmic reticulum stress marker proteins IRE1α, eIF2α and ATF6 in the macrophages were detected with Western blotting, and the mRNA levels of TGF-β, IL-6, IL-10 and TNF-α were detected with RT-PCR.
RESULTS:Estrogen treatment of the macrophages significantly decreased the expressions of M1-related proteins MHC-Ⅱ (P=0.021) and iNOS (P < 0.001) and the mRNA expressions of TNF-α (P=0.003) and IL-6 (P=0.004), increased the mRNA expression of TGF-β (P=0.002) and IL-10 (P=0.008), and up-regulated the protein expressions of IRE1α (P < 0.001) and its downstream transcription factor XBP-1 (P < 0.001). Addition of the estrogen inhibitor obviously blocked the effect of estrogen. Compared with estrogen treatment alone, combined treatment of the macrophages with estrogen and the IRE1α inhibitor 4 μ 8 C significantly up-regulated the protein expressions of MHC-Ⅱ (P=0.002) and iNOS (P=0.003) and the mRNA expressions of TNF-α (P=0.003) and IL-6 (P=0.024), and obviously down-regulated the mRNA expression of TGF-β (P < 0.001) and IL-10 (P < 0.001); these changes were not observed in cells treated with estrogen and the IRE1α agonist.
CONCLUSION:Estrogen can inhibit the differentiation of murine macrophages into a pro-inflammatory phenotype by up-regulating the IRE1α-XBP-1 signaling axis, thereby producing an inhibitory effect on inflammatory response.
