Original Article
Copyright ©2009 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Nov 28, 2009; 15(44): 5533-5540
Published online Nov 28, 2009. doi: 10.3748/wjg.15.5533
Immunotherapy for nonalcoholic steatohepatitis using the multiple cytokine production modulator Y-40138
Tatsuhiro Tsujimoto, Hideto Kawaratani, Toshiyuki Kitazawa, Hitoshi Yoshiji, Masao Fujimoto, Masahito Uemura, Hiroshi Fukui
Tatsuhiro Tsujimoto, Hideto Kawaratani, Toshiyuki Kitazawa, Hitoshi Yoshiji, Masao Fujimoto, Masahito Uemura, Hiroshi Fukui, Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Author contributions: Tsujimoto T, Kawaratani H, Kitazawa T and Uemura M performed the majority of the experiments; Tsujimoto T, Kawaratani H, Yoshiji H and Fujimoto M analyzed the data; Tsujimoto T and Fukui H designed the study and wrote the manuscript.
Supported by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, No. 19590784
Correspondence to: Tatsuhiro Tsujimoto, MD, PhD, Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan. tat-tyan@xa2.so-net.ne.jp
Telephone: +81-744-223051 Fax: +81-744-247122
Received: September 10, 2009
Revised: October 15, 2009
Accepted: October 22, 2009
Published online: November 28, 2009
Abstract

AIM: To investigate the possible use of the multiple cytokine production modulator, Y-40138, as a novel immunotherapy in the rat nonalcoholic steatohepatitis (NASH) model.

METHODS: We allocated 6-wk-old male F344 rats to choline-supplemented, L-amino acid-defined (CSAA) diet (control group), CSAA diet + Y-40138 (control + Y-40138 group), choline-deficient, L-amino acid-defined (CDAA) diet (NASH group), or CDAA diet + Y-40138 (NASH + Y-40138 group). In each group, we measured the plasma alanine aminotransferase (ALT) levels, and the plasma and liver levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-10 (IL-10). Tissue specimens of phosphate buffered saline-perfused liver were subjected to hematoxylin and eosin staining, Azan staining, Sirius red staining, and immunohistochemical staining (for Kupffer cells and TNF-α). We then extracted Kupffer cells from the collagenase-perfused livers using the Percoll gradient centrifugation method, and measured the TNF-α levels in the supernatant (in vitro TNF-α production by Kupffer cells) using an enzyme-linked immunosorbent assay kit.

RESULTS: In comparison to the NASH group, serum ALT elevation was mild, production of serum and liver TNF-α and IFN-γ was inhibited, and IL-10 production was increased in the NASH + Y-40138 group. Amelioration of liver histology was also noted in the NASH + Y-40138 group. Kupffer cell immunohistochemical staining revealed no differences between groups, whereas TNF-α immunohistochemical staining showed fewer stained cells in the NASH + Y-40138 group than in the NASH group. The TNF-α levels in the in-vitro Kupffer cell culture supernatant were lower in the NASH + Y-40138 group than in the NASH group.

CONCLUSION: Administration of Y-40138 to NASH model rats reduced hepatic inflammation and suppressed fibrosis. These results indicate that the multiple cytokine production modulator, Y-40138, is promising as a novel treatment for NASH.

Keywords: Nonalcoholic steatohepatitis, Y-40138, Tumor necrosis factor α, Interferon γ, Interleukin-10, Kupffer cell, Innate immunity