2-Methoxyestradiol protects against IgG immune complex-induced acute lung injury by blocking NF-κB and CCAAT/enhancer-binding protein β activities

Mol Immunol. 2017 May:85:89-99. doi: 10.1016/j.molimm.2017.02.007. Epub 2017 Feb 20.

Abstract

Increasing evidences indicate that 2-Methoxyestradiol (2ME2) plays an essential role in protecting against inflammatory responses. However, its effect on IgG immune complex (IC)-induced acute lung injury (ALI) remains enigmatic. In the study, by using i.p. administration of 2ME2, we evaluated its influence on IgG IC-induced pulmonary injury in mice. We found that during IgG IC-induced ALI, mice treated by 2ME2 displayed a substantial decrease in vascular permeability and neutrophil influx (represented by myeloperoxidase activity) when compared with their counterparts receiving vehicle treatment. Furthermore, 2ME2 treatment significantly decreased pro-inflammatory mediator production and inflammatory cell, especially neutrophil accumulation in bronchoalveolar lavage fluids (BALFs) upon IgG IC stimulation. In vitro, IgG IC-triggered inflammatory mediator production was markedly down-regulated by 2ME2 in macrophages. Moreover, we verified that the activation of the transcription factors, NF-κB and CCAAT/enhancer-binding protein (C/EBP) β, were inhibited by 2ME2 in IgG IC-challenged macrophages. We demonstrated that alleviation of NF-κB-dependent transcription might be associated with reduced phosphorylation of NF-κB p65, and reduction of C/EBP activation was directly linked to its expression. In addition, we discovered that IgG IC-stimulated phosphorylation of both p38 MAPK and ERK1/2 was alleviated by 2ME2. These data indicated a novel strategy for blockade of IgG IC-induced inflammatory activities.

Keywords: 2ME2; C/EBPβ; IgG immune complex; Lung injury; NF-κB.

MeSH terms

  • 2-Methoxyestradiol
  • Acute Lung Injury / immunology
  • Acute Lung Injury / metabolism*
  • Animals
  • Antigen-Antibody Complex / toxicity
  • Blotting, Western
  • CCAAT-Enhancer-Binding Protein-beta / drug effects*
  • CCAAT-Enhancer-Binding Protein-beta / immunology
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Disease Models, Animal
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacology
  • Immunoglobulin G / toxicity
  • Macrophages, Alveolar / drug effects*
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / drug effects*
  • NF-kappa B / immunology
  • NF-kappa B / metabolism
  • Real-Time Polymerase Chain Reaction

Substances

  • Antigen-Antibody Complex
  • CCAAT-Enhancer-Binding Protein-beta
  • Immunoglobulin G
  • NF-kappa B
  • Estradiol
  • 2-Methoxyestradiol