Strain difference in the induction of T‐cell activation–associated, interferon gamma–dependent hepatic injury in mice

• Published in: Hepatology (Baltimore, Md.) Vol. 27; no. 2; pp. 513 - 519
• Main Authors: Mizuhara, Hidekazu, Kuno, Masako, Seki, Nobuo, Yu, Wen‐Gong, Yamaoka, Makiko, Yamashita, Masakatsu, Ogawa, Toshikazu, Kaneda, Kenji, Fujii, Takashi, Senoh, Hachiro, Fujiwara, Hiromi
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA W.B. Saunders 01.02.1998; Wiley
• Subjects: Alanine Transaminase - blood; Animals; Biological and medical sciences; Cells, Cultured; Chemical and Drug Induced Liver Injury - etiology; Concanavalin A - pharmacology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression; Genetic Variation; Interferon-gamma - metabolism; Interleukin-2 - metabolism; Liver - drug effects; Liver - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lymphocyte Activation - drug effects; Lymphocyte Activation - physiology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Other diseases. Semiology; RNA, Messenger - analysis; Spleen - drug effects; Spleen - metabolism; Tumor Necrosis Factor-alpha - metabolism; Induction; Liver; Rodentia; Hepatic disease; Lymphokine; Experimental study; In vitro; Vertebrata; Immunology; Mammalia; Cell line; Interleukin 2; Mouse; Animal; T-Lymphocyte; Digestive diseases; Biological effect; Lesion; Tumor necrosis factor α; Gamma interferon
• DOI: 10.1002/hep.510270227
• ISSN: 0270-9139

A single intravenous injection of concanavalin A (Con A) induces T‐cell activation–associated inflammatory injury selectively in the liver. This study investigated the strain difference in the development of Con A–induced hepatic injury. Normal C57BL/6 and BALB/c spleen cells produced comparable levels of T‐cell–derived lymphokines (interferon gamma [IFN‐γ], tumor necrosis factor α [TNF‐α], and interleukin‐2 [IL‐2]) following in vitro stimulation with Con A. A single intravenous injection of Con A to C57BL/6 mice induced the plasma levels of TNF‐α and IL‐2 comparable with or slightly higher than those observed in BALB/c mice, whereas the same treatment resulted in an apparently lower level of IFN‐γ production in C57BL/6 mice. RNA from livers of Con A–treated C57BL/6 mice exhibited lower levels of IFN‐γ mRNA than RNA of BALB/c livers. Unexpectedly, a dramatic difference in the severity of hepatic injury was observed between C57BL/6 and BALB/c. Namely, the peak alanine transaminase (ALT) level was more than 15,000 U/L and inducible as early as 8 hours after injection of 0.2 mg Con A per mouse in the C57BL/6 strain, whereas the peak was approximately 3,000 U/L and induced as late as 24 hours after Con A injection in the BALB/c strain. The increase in plasma ALT levels was limited to less than 10% by injection of anti–IFN‐γ monoclonal antibody (mAb) in both strains. The C57BL/6 strain inducing lower levels of IFN‐γ exhibited higher IFN‐γ responsiveness as exemplified by the intrahepatic expression of an IFN‐γ–inducible gene, an inducible type of nitric oxide (NO) synthase (iNOS). These results indicate that, while IFN‐γ produced in vivo by activated T cells induces hepatic injury, there exists a striking strain difference in the induction of IFN‐γ–dependent hepatic injury.