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

✍ Scribed by Hidekazu Mizuhara; Masako Kuno; Nobuo Seki; Wen-Gong Yu; Makiko Yamaoka; Masakatsu Yamashita; Toshikazu Ogawa; Kenji Kaneda; Takashi Fujii; Hachiro Senoh; Hiromi Fujiwara

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 181 KB
• Volume: 27
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510270227

✦ Synopsis

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-␥], tumor necrosis factor ␣ [TNF-␣], 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-␣ 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-␥ production in C57BL/6 mice. RNA from livers of Con A-treated C57BL/6 mice exhibited lower levels of IFN-␥ 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-␥ monoclonal antibody (mAb) in both strains. The C57BL/6 strain inducing lower levels of

IFN-␥ exhibited higher IFN-␥ responsiveness as exemplified by the intrahepatic expression of an IFN-␥-inducible gene, an inducible type of nitric oxide (NO) synthase (iNOS). These results indicate that, while IFN-␥ produced in vivo by activated T cells induces hepatic injury, there exists a striking strain difference in the induction of IFN-␥-dependent hepatic injury. (HEPATOLOGY 1998; 27:513-519.)

Extensive research into the biological effects of cytokines has implied that they have a significant role in host defense/ inflammatory responses. For example, interferon gamma (IFN-␥) produced by activated T cells regulates the activation/ function of various lymphoid types of cells, 1-7 and also induces a number of other biological responses on nonlymphoid types of cells such as endothelial cells. [8][9][10][11] However, the expression of cytokines does not always lead to host defense, but sometimes produces an injurious effect depending on the amount and site of cytokines produced.

Recently, a hepatitis model was developed in which liverspecific inflammatory lesions are induced by injection of concanavalin A (Con A). 12 Our earlier studies 13,14 using this model showed that the induction of hepatic injury is associated with T-cell activation by Con A stimulation, and IFN-␥ functions as one of the critical cytokines in the pathogenesis of hepatitis. In these studies, a single mouse strain, BALB/c, was used. Recent studies have revealed that differential patterns of cytokine responses, including IFN-␥ production, among inbred mouse strains are seen in experimental infection models, resulting in different host susceptibility to infection. [15][16][17][18] In many models, C57BL/6 and BALB/c are resistant and susceptible strains, respectively, which is associated with high (C57BL/6) and low (BALB/c) levels of IFN-␥ production. 17,[19][20][21][22] These observations may raise a possibility that there also exists strain differences in the severity of Con A-induced hepatitis, because the development of hepatitis depends on IFN-␥ production.

The present study compared the level of systemic and local (hepatic) IFN-␥ production as well as the severity of hepatic injury induced following Con A stimulation between BALB/c and C57BL/6 strains. The results demonstrated that both BALB/c and C57BL/6 spleen cells produced comparable amounts of IFN-␥ following in vitro stimulation with Con A. However, C57BL/6 mice induced apparently lower levels of IFN-␥ production following in vivo Con A injection than BALB/c mice, as measured by plasma IFN-␥ concentrations and IFN-␥ mRNA expression in the liver. Surprisingly, hepatic injury induced in C57BL/6 mice was much more potent than that in BALB/c mice, although the induction of injury in both strains was dependent on IFN-␥ activity. Despite lower amounts of IFN-␥ induction, C57BL/6 mice exhibited higher levels of intrahepatic expression of an IFN-␥-inducible gene, the inducible type nitric oxide (NO) synthase (iNOS) gene. These results indicate that there exists a striking strain difference in the induction of T-cell activationassociated, IFN-␥-dependent hepatic injury, and also suggest that the difference in this model is determined by differential host susceptibility to IFN-␥ actions rather than the amount of IFN-␥ produced.