Effect of Prostaglandin E Receptor Subtype EP4 Selective Agonist on the Secretion of Tumor Necrosis Factor-α by Macrophages in Acute Ethanol-Loaded Rats


Reprint requests: Yoshihiro Nakatani, MD, The Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara-shi, Nara, 634-8522 Japan; Fax: 0744-24-7122; E-mail: ynktn@maia.eonet.ne.jp.


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.