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Int Immunopharmacol. 2019 Aug 8;75:105787. doi: 10.1016/j.intimp.2019.105787. [Epub ahead of print]

Estradiol inhibits fMLP-induced neutrophil migration and superoxide production by upregulating MKP-2 and dephosphorylating ERK.

Author information

1
Institute of Hand Surgery, Ruihua Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215100, China.
2
Department of Human Anatomy, Histology and Embryology, School of Biology and Basic Medical Sciences, Soochow University, Suzhou, Jiangsu 215007, China.
3
Department of Hand Surgery, Ruihua Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215100, China.
4
Department of Clinical Laboratory, Ruihua Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215100, China.
5
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
6
Institute of Hand Surgery, Ruihua Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215100, China; Department of Hand Surgery, Ruihua Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215100, China. Electronic address: huarui1000@163.com.

Abstract

Estrogen has been reported to inhibit neutrophil infiltration related inflammation and suppress neutrophils migration in vitro, but the underlying mechanism is not fully understood. By using HL-60 differentiated neutrophil-like cells (dHL-60) and human neutrophils, we examined the effect of 17-β estradiol (E2) on cell migration and superoxide production in response to chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) and explored the mechanisms involved. We found that fMLP significantly induced dHL-60 cell and neutrophil migration and superoxide production, which was inhibited by ERK inhibitor PD98059. E2 significantly inhibited fMLP-induced dHL-60 cell and neutrophil migration and superoxide production at both physiological and pharmacological concentrations. Mechanistic studies showed that pretreatment of these cells with E2 rapidly elevated the protein level of mitogen-activated protein kinase phosphatase 2 (MKP-2) and inhibited fMLP-induced ERK phosphorylation. Pretreatment of these cells with estrogen receptor (ER) antagonist ICI 182780 reversed the inhibition of fMP-induced cell migration and superoxide production, and the induction of MKP-2 expression and the suppression of fMP-induced ERK phosphorylation by E2. However, pretreatment of cells with G-protein coupled ER antagonist G15 had no such effect. Collectively, these results demonstrate that fMLP stimulates neutrophil chemotaxis and superoxide production through activating ERK, and indicate that ER-mediated upregulation of MKP-2 may dephosphorylate ERK and contribute to the inhibitory effect of E2 on neutrophil activation by fMLP. Our study reveals new mechanisms involved in the anti-inflammatory activity of estrogen.

KEYWORDS:

Chemotaxis; ERK; Estradiol; MKP-2; Neutrophil; Reactive oxygen species

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