15-deoxy-Δ12,14-prostaglandin J2 relieved acute liver injury by inhibiting macrophage migration inhibitory factor expression via PPARγ in hepatocyte

Weiyang Li; Jieshi Xie; Le Yang; Yuanru Yang; Lin Yang; Liying Li

doi:10.1016/j.intimp.2023.110491

15-deoxy-Δ^12,14-prostaglandin J₂ relieved acute liver injury by inhibiting macrophage migration inhibitory factor expression via PPARγ in hepatocyte

Int Immunopharmacol. 2023 Aug:121:110491. doi: 10.1016/j.intimp.2023.110491. Epub 2023 Jun 15.

Authors

Weiyang Li¹, Jieshi Xie¹, Le Yang¹, Yuanru Yang¹, Lin Yang¹, Liying Li²

Affiliations

¹ Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
² Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China. Electronic address: liliying@ccmu.edu.cn.

PMID: 37329807
DOI: 10.1016/j.intimp.2023.110491

Abstract

15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) exhibited potential to alleviate liver inflammation in chronic injury but was less studied in acute injury. Acute liver injury was associated with elevated macrophage migration inhibitory factor (MIF) levels in damaged hepatocytes. This study aimed to investigate the regulatory mechanism of hepatocyte-derived MIF by 15d-PGJ₂ and its subsequent impact on acute liver injury. In vivo, mouse models were established by carbon tetrachloride (CCl₄) intraperitoneal injection, with or without 15d-PGJ₂ administration. 15d-PGJ₂ treatment reduced the necrotic areas induced by CCl₄. In the same mouse model constructed using enhanced green fluorescent protein (EGFP)-labeled bone marrow (BM) chimeric mice, 15d-PGJ₂ reduced CCl₄ induced BM-derived macrophage (BMM, EGFP⁺F4/80⁺) infiltration and inflammatory cytokine expression. Additionally, 15d-PGJ₂ down-regulated liver and serum MIF levels; liver MIF expression was positively correlated with BMM percentage and inflammatory cytokine expression. In vitro, 15d-PGJ₂ inhibited Mif expression in hepatocytes. In primary hepatocytes, reactive oxygen species inhibitor (NAC) showed no effect on MIF inhibition by 15d-PGJ₂; PPARγ inhibitor (GW9662) abolished 15d-PGJ₂ suppressed MIF expression and antagonists (troglitazone, ciglitazone) mimicked its function. In Pparg silenced AML12 cells, the suppression of MIF by 15d-PGJ₂ was weakened; 15d-PGJ₂ promoted PPARγ activation in AML 12 cells and primary hepatocytes. Furthermore, the conditioned medium of recombinant MIF- and lipopolysaccharide-treated AML12 respectively promoted BMM migration and inflammatory cytokine expression. Conditioned medium of 15d-PGJ₂- or siMif-treated injured AML12 suppressed these effects. Collectively, 15d-PGJ₂ activated PPARγ to suppress MIF expression in injured hepatocytes, reducing BMM infiltration and pro-inflammatory activation, ultimately alleviating acute liver injury.

Keywords: Bone marrow derived macrophage; Inflammation; Migration; Pro-inflammatory activation.

MeSH terms

Animals
Chemical and Drug Induced Liver Injury* / drug therapy
Culture Media, Conditioned
Hepatocytes
Liver
Macrophage Migration-Inhibitory Factors* / metabolism
Mice
PPAR gamma
Prostaglandin D2* / pharmacology
Prostaglandin D2* / therapeutic use
Prostaglandins

Substances

Culture Media, Conditioned
Macrophage Migration-Inhibitory Factors
PPAR gamma
Prostaglandin D2
Prostaglandins