T cell activation-associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6.

作者：Hidekazu Mizuhara, Emily T. O’Neill, Nobuo Seki, Toshikazu Ogawa, Chihiro Kusunoki, Keiichi Otsuka, S Satoh, Mineo Niwa, Hachiro SENOH, H Fujiwara · 发表于：The Journal of Experimental Medicine · 年份：1994 · DOI：10.1084/jem.179.5.1529 · 被引用次数：518 · 研究领域：Vitamin C and Antioxidants Research、Macrophage Migration Inhibitory Factor、Drug-Induced Hepatotoxicity and Protection

This study investigates the molecular mechanisms underlying the induction of and protection from T cell activation-associated hepatic injury. When BALB/c mice were given a single intravenous injection of concanavalin A (Con A) (> or = 0.3 mg/mouse), they developed acute hepatic injury as assessed by a striking increase in plasma transaminase levels within 24 h. Histopathologically, only the liver was injured while moderate infiltration of T cells and polymorphonuclear cells occurred in the portal areas and around the central veins. The induction of hepatic injury was dependent on the existence as well as the activation of T cells, as untreated BALB/c nu/nu mice or BALB/c mice pretreated with a T cell-specific immunosuppressive drug, FK506, failed to develop disease. Significant increases in the levels of various cytokines in the plasma were detected before an increase in plasma transaminase levels. Within 1 h after Con A injection, tumor necrosis factor (TNF) levels peaked, this being followed by production of two other inflammatory cytokines, interleukin 6 (IL-6) and IL-1. Passive immunization with anti-TNF but not with anti-IL-1 or anti-IL-6 antibody, conferred significant levels of protection. Moreover, administration of rIL-6 before Con A injection resulted in an IL-6 dose-dependent protection. A single administration of a given dose of rIL-6 completely inhibited the release of transaminases, whereas the same regimen induced only 40-50% inhibition of TNF production. More ...