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

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.