Immunotherapy for nonalcoholic steatohepatitis using the multiple cytokine production modulator Y-40138

• Published in: World journal of gastroenterology : WJG 2009-11, Vol.15 (44), p.5533-5540
• Main Authors: Tsujimoto, Tatsuhiro, Kawaratani, Hideto, Kitazawa, Toshiyuki, Yoshiji, Hitoshi, Fujimoto, Masao, Uemura, Masahito, Fukui, Hiroshi
• Format: Article
• Language: English
• Subjects: Acetamides - pharmacology; Alanine Transaminase - blood; Animals; Collagenases - chemistry; Cytokines - antagonists & inhibitors; Cytokines - blood; Enzyme-Linked Immunosorbent Assay - methods; Fatty Liver - therapy; Immunohistochemistry - methods; Immunotherapy - methods; Interferon-gamma - blood; Interleukin-10 - blood; Kupffer Cells - drug effects; Male; Original; Piperazines - pharmacology; Rats; Rats, Inbred F344; Tumor Necrosis Factor-alpha - blood; 细胞因子; 酒精性
• ISSN: 1007-9327; 2219-2840
• DOI: 10.3748/wjg.15.5533

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.