Critical roles of TRAIL in hepatic cell death and hepatic inflammation
Shi-Jun Zheng, Pu Wang, Galit Tsabary, Youhai H. Chen
Shi-Jun Zheng, Pu Wang, Galit Tsabary, Youhai H. Chen
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Article Immunology

Critical roles of TRAIL in hepatic cell death and hepatic inflammation

Abstract

The TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis of tumor cells but not most normal cells. Its role in hepatic cell death and hepatic diseases is not clear. In vitro studies suggest that murine hepatocytes are not sensitive to TRAIL-induced apoptosis, indicating that TRAIL may not mediate hepatic cell death. Using two experimental models of hepatitis, we found that hepatic cell death in vivo was dramatically reduced in TRAIL-deficient mice and mice treated with a blocking TRAIL receptor. Although both TRAIL and its death receptor 5 were constitutively expressed in the liver, TRAIL expression by immune cells alone was sufficient to restore the sensitivity of TRAIL-deficient mice to hepatitis. Thus, TRAIL plays a crucial role in hepatic cell death and hepatic inflammation.

Authors

Shi-Jun Zheng, Pu Wang, Galit Tsabary, Youhai H. Chen

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Serum transaminase and liver fibrosis in Con-A–induced hepatitis. (a–d) ...
Serum transaminase and liver fibrosis in Con-A–induced hepatitis. (a–d) Normal (TRAIL+/+) and TRAIL-deficient (TRAIL–/–) BALB/c mice, five per group, were injected once with Con-A (0–25 mg/kg of body weight) as described in Methods. Serum transaminase levels were determined 8 and 24 hours after the Con-A injection. The ALT and AST levels are presented in Sigma-Frankel units. The differences between the two groups are statistically significant as determined by ANOVA (P < 0.001). (e–g) TRAIL–/– and TRAIL+/+ mice, three per group, were injected with a low dose of Con-A (8 mg/kg of body weight) in PBS once a week for 6 consecutive weeks (25). Control mice received only PBS injections. One week after the last injection, mice were sacrificed and serum transaminase activities determined (e and f). The degree of fibrosis was determined by measurement of the amount of collagen per milligram of total liver proteins as previously described (24). The differences between the two groups after Con-A injections are statistically significant (P < 0.05) for AST and ALT, but not for collagen.