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Effect of Prostaglandin E Receptor Subtype EP4 Selective Agonist on the Secretion of Tumor Necrosis Factor‐α by Macrophages in Acute Ethanol‐Loaded Rats
Author(s) -
Nakatani Yoshihiro,
Kitazawa Toshiyuki,
Fujimoto Masao,
Tamura Nobuhiro,
Uemura Masahito,
Yamao Junichi,
Fukui Hiroshi
Publication year - 2004
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2004.tb03229.x
Subject(s) - tumor necrosis factor alpha , secretion , agonist , endocrinology , medicine , proinflammatory cytokine , receptor , macrophage , kupffer cell , chemistry , immunology , inflammation , in vitro , biochemistry
Background: It is suggested that endotoxin and proinflammatory cytokines play an important role in the development and progression of alcoholic liver disease. Recently, a prostaglandin receptor subtype EP4 agonist with cytoprotective effect has been developed. We examined the efficacy of an EP4 agonist ONO‐AE1‐437 on tumor necrosis factor‐α (TNF‐α) secretion of Kupffer cells, splenic macrophages, and alveolar macrophages in acute ethanol‐loaded rats. Methods: Kupffer cells, splenic macrophages, and alveolar macrophages were isolated from control and acute ethanol‐loaded rats (5 mg/g body weight of ethanol, intraperitoneally). After the preculture in the medium that containing 0, 0.1, 1, 10, or 100 nmol/liter of ONO‐AE1‐437, TNF‐α secretion of these cells stimulated by 100 ng/ml of endotoxin was determined for 3 hr. Results: The amount of TNF‐α secreted from alveolar macrophages was largest in both the control and the acute ethanol‐loaded rats. Acute ethanol load enhances TNF‐α secretion of splenic macrophages. The addition of ONO‐AE1‐437 significantly inhibited TNF‐α secretion of Kupffer cells and splenic macrophages in both the control and the acute ethanol‐loaded rats. Alveolar macrophages were less affected. Conclusions: An EP4 agonist ONO‐AE1‐437 suppresses excess TNF‐α secretion from macrophages and seems promising for future trial in patients with severe alcoholic hepatitis.