EFFECT OF FK506 ON THE ACTIVATION STATE OF HEPATIC MACROPHAGES IN PROPIONIBACTERIUM ACNES-TREATED RATS

Activated hepatic macrophages can provoke massive liver necrosis follo wing endotoxin stimulation through microcirculatory disturbances due t o sinusoidal fibrin deposition in rats pretreated with heat-killed Pro pionibacterium acnes. In these rats, FK506 (tachlorinus) administered 24 h before and at the time of endotoxin injection, significantly atte nuated liver injury compared with the rats given no FK506. The effect of FK506 on hepatic macrophage activation and its action sites were st udied in Propionibacterium acnes-treated rats. When rats received Prop ionibacterium acnes intravenously, hepatic-mRNA expression of interfer on-gamma-inducing factor and interleukin-2 and splenic-mRNA expression of interferon-gamma were significantly increased compared with normal rats. Hepatic-mRNA expression of CD14, a receptor for lipopolysacchar ide and its binding protein complex, was also increased preceding the expressions of the three cytokines in the liver and spleen. FK506 admi nistration attenuated hepatic-mRNA expression of interleukin-2 and bot h superoxide anions as well as tumour necrosis factor-a production by hepatic macrophages, but did not change CD14-mRNA expression in Propio nibacterium acnes-treated rats. It is suggested that a cytokine networ k through interferon-gamma-inducing factor, interferon-gamma and inter leukin-2 may operate during activation of hepatic macrophages in rats treated with heat-killed Propionibacterium acnes, while CD14 expressio n on the cells may increase independently of this network. FK506 seems to attenuate such activation by suppressing hepatic interleukin-2 exp ression, without affecting CD14 expression on the cells.