title: 2-Methoxyestradiol protects against IgG immune complex-induced acute lung injury by blocking NF-κB and CCAAT/enhancer-binding protein β activities.
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.
authors.affiliation: Department of Pathogenic Biology and Immunology, Medical School of Southeast University, Nanjing, 210009, China. Electronic address: ycgagcy@163.com.
authors.forename: Chunguang
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Bioengineering, Medical School of Southeast University, Nanjing, 210009, China.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Pathogenic Biology and Immunology, Medical School of Southeast University, Nanjing, 210009, China.
authors.forename: Qiqing
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Intensive Care, Jintan Hospital, Jiangsu University, Changzhou, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Yuan
authors.affiliation: Zhejiang Respiratory Drugs Research Laboratory of the State Food and Drug Administration of China, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Huifang
authors.initials: H
authors.lastname: Tang
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative & Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States. Electronic address: hgao2@partners.org.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Gao
mesh_terms: D000077584:2-Methoxyestradiol; D055371:Acute Lung Injury / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000936:Antigen-Antibody Complex / Q000633:toxicity; D015153:Blotting, Western; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D007074:Immunoglobulin G / Q000633:toxicity; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000936:Antigen-Antibody Complex; D022782:CCAAT-Enhancer-Binding Protein-beta; D007074:Immunoglobulin G; D016328:NF-kappa B; D004958:Estradiol; D000077584:2-Methoxyestradiol
keywords: 2ME2; C/EBPβ; IgG immune complex; Lung injury; NF-κB