Therapeutic effects of cytokine modulator Y-40138 in the rat alcoholic liver disease model.
OBJECTIVE
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.
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
Hideto
H
Kawaratani
Tatsuhiro
T
Tsujimoto
Toshiyuki
T
Kitazawa
Hitoshi
H
Yoshiji
Masahito
M
Uemura
Hiroshi
H
Fukui
D000081:Acetamides / Q000494:pharmacology*; D000199:Actins / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood* / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000097:blood*; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000081:Acetamides; D000199:Actins; D000410:Alanine Transaminase; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D007371:Interferon-gamma; D016753:Interleukin-10; D010879:Piperazines; D012333:RNA, Messenger; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; C406663:Y 39041; C498862:Acta2 protein, rat