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

Abstract

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-gamma], tumor necrosis factor alpha [TNF-alpha], 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-alpha 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-gamma production in C57BL/6 mice. RNA from livers of Con A-treated C57BL/6 mice exhibited lower levels of IFN-gamma 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-gamma monoclonal antibody (mAb) in both strains. The C57BL/6 strain inducing lower levels of IFN-gamma exhibited higher IFN-gamma responsiveness as exemplified by the intrahepatic expression of an IFN-gamma-inducible gene, an inducible type of nitric oxide (NO) synthase (iNOS). These results indicate that, while IFN-gamma produced in vivo by activated T cells induces hepatic injury, there exists a striking strain difference in the induction of IFN-gamma-dependent hepatic injury.

Indispensable Role for TNF-α and IFN-γ at the Effector Phase of Liver Injury Mediated by Th1 Cells Specific to Hepatitis B Virus Surface Antigen

“…As we have shown previously, C57BL/6 mice are more susceptible than BALB/c mice to P. acnes plus LPS-induced liver injury (8). Similar strain differences were reported for the Con A-liver injury model (25). Conversely, BALB/c mice are susceptible to Leishmania major infection whereas C57BL/6 mice are resistant (26 -28).…”

Liver-Specific Alpha 2 Interferon Gene Expression Results in Protection from Induced Hepatitis

“…293 and 293Cre4 cells (23) were grown in minimal essential medium (MEM) supplemented with 10% heat-inactivated fetal calf serum (FCS). 911 (human embryonic retinoblasts), L-929 (mouse fibroblasts), and HuH-7 (human hepatoma) cells were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% FCS.…”

TNF-α-Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1—Relevance for Concanavalin A-Induced Hepatitis

“…The dose of Con A was 20 and 18 mg/kg in BALB/c mice and TNFR Ϫ/Ϫ mice, respectively (because of the lower sensitivity of BALB/c mice toward Con A-induced liver injury; Ref. 21). rmuTNF (kindly provided by Dr. G. R. Adolf, Bender & Co, Vienna, Austria) was injected i.v.…”