Gadolinium chloride (GdCl3) reportedly inhibits Kupffer cell function including
TNF-alpha production and thereby improves organ dysfunctions after LPS challenge, particularly in partially hepatectomized (PH) mice. In addition,
TNF-alpha reportedly promotes the regeneration of hepatocytes after PH. However, we have frequently seen GdCl3 treatment increase the mortality of normal mice after LPS injection. Therefore, we investigated this controversial issue in the present study. The mice treated by GdCl3 (10 mg/kg, i.v.) at 24 h before LPS challenge showed increased serum
TNF-alpha and ALT levels after LPS challenge and a decreased mouse survival rate. The Kupffer cells from GdCl3-treated mice consistently produced a much larger amount of
TNF-alpha following in vitro LPS stimulation than those of the control mice despite the fact that the Kupffer cells decreased in number and also demonstrated decreased
superoxide production. Anti-
TNF-alpha Ab before LPS-injection greatly improved GdCl3-induced mouse mortality and the degree of liver injury. In marked contrast, the increased amount of
TNF-alpha induced by GdCl3 improved the survival after LPS challenge in PH mice because
TNF-alpha promoted hepatocyte mitosis/regeneration in PH liver as evidenced by the fact that the inhibition of
TNF-alpha before PH suppressed hepatocyte regeneration and decreased survival after LPS challenge. In conclusion, GdCl3 depletes the
superoxide-producing Kupffer cells but conversely enhances the function of
TNF-alpha-producing Kupffer cells, which thereby leads to LPS-induced mortality. Meanwhile, the increased
TNF-alpha production induced by GdCl3 supports liver regeneration and increases the survival after LPS challenge in PH mice.