Critical roles of TRAIL in hepatic cell death and hepatic inflammation
Shi-Jun Zheng, … , Galit Tsabary, Youhai H. Chen
Shi-Jun Zheng, … , Galit Tsabary, Youhai H. Chen
Published January 1, 2004
Citation Information: J Clin Invest. 2004;113(1):58-64. https://doi.org/10.1172/JCI19255.
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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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Figure 1

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TRAIL–/– mice are resistant to Con-A–induced hepatitis. Normal (TRAIL+/+...
TRAIL–/– mice are resistant to Con-A–induced hepatitis. Normal (TRAIL+/+) and TRAIL-deficient (TRAIL–/–) BALB/c mice, five per group, were injected once with Con-A (25 mg/kg of body weight) to induce hepatitis as described in Methods. Mice were sacrificed at different time points after the Con-A injection, and livers were harvested and tested as described in Methods. (a and b) Livers from TRAIL+/+ and TRAIL–/– mice, respectively, 24 hours after Con-A injection. (c and d) H&E staining of liver sections from TRAIL+/+ and TRAIL–/– mice, respectively, 24 hours after Con-A injection. The arrowhead indicates massive cell death in the TRAIL+/+ liver section. Original magnification, ×200. (e and f) TUNEL staining of liver sections from TRAIL+/+ and TRAIL–/– mice, respectively, 24 hours after Con-A injection. The arrowhead indicates an aggregate of apoptotic cells in the TRAIL+/+ liver section (apoptotic nuclei are shown in brown). Original magnification, ×200. (g) Numbers of apoptotic cells per square millimeter of liver sections of TRAIL+/+ and TRAIL–/– mice 24 hours after Con-A injection. The difference between the two groups is statistically significant (P < 0.0001). (h) Caspase-3 activity in the liver cytosolic protein extract at different time points after Con-A injection. The difference between the two groups is statistically significant (P < 0.01). Results shown are from one representative experiment of three.