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

Abstract

SummaryThis 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) (>10.3 rag/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 rlL-6 before Con A injection resulted in an IL-6 dose-dependent protection. A single administration of a given dose of rlL-6 completely inhibited the release of transaminases, whereas the same regimen induced only 40-50% inhibition of TNF production. More than 80% inhibition of TNF production required four consecutive rlL-6 injections. These results indicate that: (a) TNFs are critical cytokines for inducing T cell activation-associated (Con A-induced) hepatitis; (b) the induction of hepatitis is almost completely controlled by rlL-6; and (c) rlL-6 exerts its protective effect through multiple mechanisms including the reduction of TNF production.

Protection from concanavalin A (Con A)-induced T cell-dependent hepatic lesions and modulation of cytokine release in mice by sodium fusidate

“…Our present observation that immunoinflammatory hepatitis can be induced in mice by a single i.v injection of Con A further confirms the original data by Tiegs' group [1,2], which were independently reproduced by others [3,8]. Most histological and immunopathogenic pathways described in those studies were also observed here.…”

“…Hence, the histological and serological protection afforded by SF was accompanied by modifications of cytokine plasma levels, including reduced levels of IL-2, IFN-g and TNF-a, and augmented levels of IL-6. In this model TNF-a and IL-6 play a pathogenic and protective role [1][2][3], and the inhibition of TNF-a, with the simultaneous increase of IL-6 levels, may thus be central to the beneficial effects of SF. The ability of SF to reduce the blood levels of IL-2 and IFN-g may also be related to the protection afforded in this model by CsA and FK506, two immunosuppressants which selectively block IL-2 and IFN-g production [21].…”

“…Because Con A-induced hepatitis develops with simultaneous elevation in the circulation of several macrophage-and T cellderived cytokines [1][2][3], and since this may control or reflect the progression of the immunoinflammatory syndrome, we next examined if SF interfered with the systemic levels of these molecules. Two groups of mice, treated with either PBS or SF (80 mg/kg) 24 h and 1 h before Con A application, were killed before Con A injection (T0) and 2, 4 and 8 h thereafter.…”

“…Nonetheless, the role of cytokines in the pathogenesis of this immunoinflammatory condition remains to be defined. For example, the disease is equally prevented by anti-TNF-a antibody [2,3] and IL-6 [3], and the outcome of the disease may therefore depend on a fine balance between pro-and anti-inflammatory cytokines released by Con A-activated cells.…”

Mice deficient in hepatocyte‐specific IL‐1Ra show delayed resolution of concanavalin A‐induced hepatitis

“…Consistently with previous data, we observed that circulating levels of other inflammatory cytokines, such as IL-6, IL-1β, and IFN-γ peaked 3 h after ConA injection, and decreased sharply at later time points (Supporting Information Fig. 2A) [14]. In liver extracts, IL-1Ra levels increased gradually until 24 h after ConA injection, remained elevated up to 72 h, and returned to basal levels thereafter.…”