Therapeutic effects of cytokine modulator Y-40138 in the rat alcoholic liver disease model.

Abstract

BACKGROUND AND AIM:

Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interferon-gamma (IFN-γ), induce liver injury in the rat alcoholic liver disease (ALD) model. Y-40138 is known to suppress the pro-inflammatory cytokines and augment the anti-inflammatory cytokines. We investigated whether or not Y-40138 may be effective as a novel immunotherapy in the rat ALD model.

METHODS:

Male Wistar rats were fed Lieber-DeCarli ethanol liquid diet. The effects of Y-40138 treatment in the ALD models were assessed by analyzing the serum and the liver tissues.

RESULTS:

The serum levels of alanine aminotransferase (ALT), TNF-α, and IFN-γ, and the liver levels of TNF-α and IFN-γ were significantly higher in the ethanol-fed group than in the pair-fed group. The immunohistochemistry of the liver TNF-α and 4-hydroxynonenal (4HNE), and the expressions of TNF-α and IFN-γ mRNA were increased, too. The gene expressions of interleukin-10 (IL-10) in the ethanol-fed group were suppressed as compared with the pair-fed group. The serum triglyceride (TG) and liver TG were increased, and Oil Red O and α-smooth muscle actin (α-SMA) staining showed greater expression by ethanol-fed feeding. After administration of Y-40138, enzyme linked immunosorbent assay and real-time polymerase chain reaction of the liver showed that the increased TNF-α and IFN-γ were suppressed, and that IL-10 was augmented. Moreover, ethanol-induced lipid accumulation in the liver was suppressed by administering Y-40138.

CONCLUSIONS:

Y-40138 decreased the inflammation, fibrosis, oxidative stress, and lipid synthesis, and augmented the anti-inflammatory cytokines of the liver. These results indicate that the multiple cytokine production modulator, Y-40138, is a promising novel therapy for ALD.

• Authors: Hideto Kawaratani, Tatsuhiro Tsujimoto, Toshiyuki Kitazawa, Hitoshi Yoshiji, Masahito Uemura, Hiroshi Fukui
• Journal: Journal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 26 Issue 4 Pg. 775-83 (Apr 2011) ISSN: 1440-1746 [Electronic] Australia
• PMID: 21251062 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Chemical References

• Acetamides
• Actins
• Anti-Inflammatory Agents
• Cytokines
• Inflammation Mediators
• Piperazines
• RNA, Messenger
• Triglycerides
• Tumor Necrosis Factor-alpha
• Y 39041
• smooth muscle actin, rat
• Interleukin-10
• Interferon-gamma
• Alanine Transaminase

Topics

• Acetamides (pharmacology)
• Actins (metabolism)
• Alanine Transaminase (blood)
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Cytokines (blood, genetics)
• Disease Models, Animal
• Down-Regulation
• Enzyme-Linked Immunosorbent Assay
• Immunohistochemistry
• Inflammation Mediators (blood)
• Interferon-gamma (blood)
• Interleukin-10 (blood)
• Liver (drug effects, immunology, metabolism, pathology)
• Liver Diseases, Alcoholic (blood, drug therapy, immunology, pathology)
• Male
• Piperazines (pharmacology)
• RNA, Messenger (metabolism)
• Rats
• Rats, Wistar
• Reverse Transcriptase Polymerase Chain Reaction
• Triglycerides (blood)
• Tumor Necrosis Factor-alpha (blood)