INDUCTION OF METALLOTHIONEIN BY SUPERANTIGENIC BACTERIAL EXOTOXIN - PROBABLE INVOLVEMENT OF THE IMMUNE-SYSTEM

Metallothionein (MT) can be induced in mouse liver by a bacterial exot oxin, toxic shock syndrome toxin-1 (TSST-1). Hepatic MT was induced by TSST-1 in a dose-dependent manner from 100 mu g/kg through 3 mg/kg in CF-1 mice, and by 6 h the induction was almost maximal. The increase of hepatic MT occurred at the mRNA level, also, and both MT-I and II m RNAs increased coordinately. Because TSST-1 is a superantigen, it was investigated whether TSST-1 induces MT through cytokines as a conseque nce of immunostimulation. In low-cytokine-producing mice (C3H/HeJ), up to a dose of 1 mg/kg of TSST-1, there was only 2- to 3-fold increase of hepatic MT. In contrast, in normal-cytokine-producing mice (C3Heb/F eJ), TSST-1 increased MT in a dose-dependent manner, and at a dose of 1 mg/kg, there was a 25-fold increase in hepatic MT. This suggests tha t activation of the immune system is probably involved in the inductio n of MT by TSST-1. Studies on the role of specific hepatic cytokines ( IL-1, TNF-alpha, and IL-6) in TSST-mediated hepatic MT induction showe d that TSST-1 did not increase hepatic IL-1 or TNF-alpha significantly over controls in any of the mouse strains studied. In contrast, TSST- 1 induced hepatic IL-6 in all three strains of mice. However, in CF-1 and C3Heb/FeJ mice (normal-cytokine-producing) IL-6 induction preceded MT mRNA induction, but in C3H/HeJ mice (low-cytokine-producing), IL-6 induction did not precede MT mRNA induction.