Effect of prostaglandin E receptor subtype EP4 selective agonist on the secretion of tumor necrosis factor-alpha by macrophages in acute ethanol-loaded rats

• Published in: Alcoholism, clinical and experimental research Vol. 28; no. 8 Suppl Proceedings; pp. 123S - 128S
• Main Authors: Nakatani, Yoshihiro, Kitazawa, Toshiyuki, Fujimoto, Masao, Tamura, Nobuhiro, Uemura, Masahito, Yamao, Junichi, Fukui, Hiroshi
• Format: Journal Article
• Language: English
• Published: England 01.08.2004
• Subjects: Animals; Ethanol - administration & dosage; Macrophages - drug effects; Macrophages - metabolism; Male; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E - agonists; Receptors, Prostaglandin E - physiology; Receptors, Prostaglandin E, EP4 Subtype; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0145-6008
• DOI: 10.1097/01.ALC.0000133541.13670.58

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-alpha (TNF-alpha) secretion of Kupffer cells, splenic macrophages, and alveolar macrophages in acute ethanol-loaded rats. 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-alpha secretion of these cells stimulated by 100 ng/ml of endotoxin was determined for 3 hr. The amount of TNF-alpha secreted from alveolar macrophages was largest in both the control and the acute ethanol-loaded rats. Acute ethanol load enhances TNF-alpha secretion of splenic macrophages. The addition of ONO-AE1-437 significantly inhibited TNF-alpha secretion of Kupffer cells and splenic macrophages in both the control and the acute ethanol-loaded rats. Alveolar macrophages were less affected. An EP4 agonist ONO-AE1-437 suppresses excess TNF-alpha secretion from macrophages and seems promising for future trial in patients with severe alcoholic hepatitis.