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

Abstract

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-alpha (TNF-alpha) 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-alpha secretion of these cells stimulated by 100 ng/ml of endotoxin was determined for 3 hr.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Yoshihiro Nakatani, Toshiyuki Kitazawa, Masao Fujimoto, Nobuhiro Tamura, Masahito Uemura, Junichi Yamao, Hiroshi Fukui
• Journal: Alcoholism, clinical and experimental research (Alcohol Clin Exp Res) Vol. 28 Issue 8 Suppl Proceedings Pg. 123S-128S (Aug 2004) ISSN: 0145-6008 [Print] England
• PMID: 15318098 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Receptors, Prostaglandin E
• Receptors, Prostaglandin E, EP4 Subtype
• Tumor Necrosis Factor-alpha
• Ethanol

Topics

• Animals
• Ethanol (administration & dosage)
• Macrophages (drug effects, metabolism)
• Male
• Rats
• Rats, Sprague-Dawley
• Receptors, Prostaglandin E (agonists, physiology)
• Receptors, Prostaglandin E, EP4 Subtype
• Tumor Necrosis Factor-alpha (metabolism)