Objective and design: To explore the mechanisms by which liver-infiltrating T lymphocytes cause hepatocyte damage in the liver injury induced by delayed-type hypersensitivity to picryl chloride.
Materials and methods: Nonparenchymal cells (NPC) were isolated 12 h after liver injury elicitation and fractionated into Kupffer cell-enriched (Fr. A) and lymphocyte-enriched populations (Fr. B). They were used as the effectors for coculture with hepatocytes.
Results: The cells in total NPC and Fr. B harvested at 12 h of liver injury were increased two- and six-fold respectively compared with those at 0 h. Fr. B, mainly including CD4+ and CD8+ T cells, exhibited a significantly stronger hepatotoxicity than total NPC did, while Fr.A did not. NPC at 12 h showed remarkably increased matrix metalloproteinase-2 and -9 activities indicative of infiltration potential through extracellular matrix. When NPC and hepatocytes were cultured in separated compartments in Transwell chamber, no hepatotoxicity was observed. However, 30 min-pre-contact with hepatocytes as stimulator significantly triggered NPC hepatotoxicity. The acquisition of such hepatotoxic potential was significantly abolished by anti-LFA-1 pretreatment for NPC or anti-ICAM-1 treatment for hepatocytes before contact. Both aprotonin and superoxide dismutase dose-dependently inhibited the hepatotoxicity.
Conclusions: Liver-infiltrating T lymphocytes may be triggered by hepatocytes via LFA-1/ICAM-1 interaction to release toxic substances, such as proteases and oxygen radicals, which consequently lead to the hepatocyte damage.