largely unknown what kind of molecules and what kind of Concanavalin A (Con A) induces T-cell-mediated heregulation are critically involved in the hepatic injury. It has patic injury in vivo, although Con A-stimulated lymphobecome generally accepted that activated T lymphocytes are cytes are not cytotoxic to normal hepatocytes in vitro.
involved in both acute and chronic hepatitis and the patho-This contradiction makes the mechanism of Con A-ingenesis of cirrhosis. 1 Therefore, animal models of T-cell-meduced hepatitis elusive. In this study, we demonstrate diated hepatitis are thought to reflect human clinical hepatithat Con A but not tumor necrosis factor a (TNF-a), intis or hepatocellular damage situations. Recently, a hepatitis terferon gamma (IFN-g), or actinomycin D (ActD) inmodel was developed in which liver-specific inflammatory duced the susceptibility of hepatocytes to activated aulesions were induced by the injection of concanavalin A (Con tologous lymphocyte cytotoxicity. Con A sensitized A) without pretreatment by a specific hepatotoxic agent such hepatocytes within 30 minutes after the stimulation in as D-galactosamine. 2 Con A-induced murine hepatitis has a dose-dependent fashion. The cytotoxicity was dose-deprovided a novel model, in that hepatitis is induced as a pendently inhibited by either a Con A ligand, a-methyl consequence of T-cell activation. 2 However, the mechanism mannoside, or a perforin inhibitor, concanamycin A of the model has not been investigated because activated T (CMA), but not by anti-Fas ligand antiserum. In addition, cells themselves do not damage the autologous hepatocytes in Con A-treated hepatocytes were not sensitive to autolovitro. Several endogenous mediators such as tumor necrosis gous activated lymphocytes from a perforin-deficient factor a (TNF-a) have been reported to be involved in the mouse, while hepatocytes from lpr mice were sensitized pathogenesis of the model, 3,4 although these mediators are by Con A. In fact, Con A did not induce liver injury in not directly cytotoxic to hepatocytes in the absence of tranperforin-deficient mice within the concentration emscriptional arrest reagents. Previous reports show that Con ployed in this study. Therefore, we conclude that the A binds strongly to the hepatocyte plasma membrane 5,6 and cytotoxicity was mediated through perforin/granzymes accumulates in the liver. 4 Therefore, it is possible that Con but not through the Fas/Fas ligand pathway. The cyto-A causes a direct biological change in hepatocytes, which toxicity was inhibited by anti-intercellular adhesion results in hepatic injury by activated lymphocytes. The inducmolecule-1 (ICAM-1)/LFA-1 antibodies, but not by antition and maintenance of inflammation requires the adhesion VCAM-1/VLA-4 antibodies, both in vitro and in vivo. The of leukocytes to target cells. Even though it has been estabcytotoxicity appears to be caused by CD8 / T cells; howlished that the interaction via adhesion molecules between ever, the cytokines from activated CD4 / T cells play a lymphocytes and endothelial cells plays an important role in critical role in the pathogenesis of the hepatitis in vivo, the onset of inflammation, [7][8][9] little is known about the adhebecause administration of anti-IFN-g antibodies inhibsion between hepatocytes and lymphocytes. Volpes et al. inited the occurrence of the hepatitis. In conclusion, Con vestigated the role of cell-adhesion molecules in acute and A-induced hepatitis is thought to be dominantly medichronic liver inflammation, 10 and they found that intercelluated by a perforin-dependent pathway through ICAM-1/ lar adhesion molecule-1 (ICAM-1) expression by hepatocytes LFA-1 interaction. (HEPATOLOGY 1996;24:702-710.) correlated well with the degree of liver inflammation. 11 In previous studies, we demonstrated that hepatocytes express ICAM-1 and VCAM-1 after stimulation with lymphokines Hepatitis is an inflammatory liver disease induced by various causes (virus infection, bacterial infection, alcohol, drug and bind T lymphocytes via the adhesion molecules. 12,13 In this study, we examined the mechanism of Con A-in-injury, etc.). Although there are many unsolved problems related to the mechanisms, it is clear that hepatocytes are duced hepatic injury and the role of adhesion molecules on hepatocytes in the model. We found that Con A sensitized the major target cells damaged in hepatitis. However, it is hepatocytes to the autologous activated lymphocytes via perforin-mediated, but not Fas-mediated, cytotoxicity, and that ICAM-1/LFA-1 interaction and interferon gamma (IFN-g) Abbreviations: Con A, concanavalin A; TNF-a, tumor necrosis factor a; ICAM-1, intercel-play critical roles in the pathogenesis of Con A-induced heplular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; LFA-1, lymphocyte atitis. function-associated antigen-1; IFN-g, interferon gamma; IL, interleukin; VLA-4, very late antigen-4; LDH, lactate dehydrogenase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tet-
Methods
razolium bromide; AST, aspartate transaminase; ALT, alanine transaminase; ActD, actinomycin D; E/T, effector-to-target ratio; CyH, cycloheximide; CMA, concanamycin A.