Opposite Effects of Enhanced Tumor Necrosis Factor-?? Production From Kupffer Cells by Gadolinium Chloride on Liver Injury/Mortality in Endotoxemia of Normal and Partially Hepatectomized Mice

Abstract

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.

Inactivation of Kupffer cells by gadolinium administration prevents lipopolysaccharide-induced decrease in liver insulin-like growth factor-I and IGF-binding protein-3 gene expression

“…Furthermore, Kono et al (2002) have reported that although gadolinium administration prevented LPS-induced increase in TNF-gene expression in the liver, it did not modify the serum concentrations of TNF-. However, it has recently been reported that gadolinium treatment decreased superoxide generation, but conversely increased Kupffer cell TNF-production after LPS stimulation (Kinoshita et al 2005). These data indicate that gadolinium treatment decreases phagocytosis and superoxide production in Kupffer cells, whereas its effect on TNFand cytokine release is less clear.…”

Diverse Enhancement of Superoxide Production from Kupffer Cells and Neutrophils after Burn Injury or Septicemia

“…The superoxide production from Kupffer cells was determined by MCLA-dependent chemiluminescence using the method of Nakano [16,19,20]. A glass cuvette containing isolated Kupffer cells (1 × 10 5 ) and MCLA (2 µM) in 2.0 ml of HBSS was placed in a luminescence reader (BLR-101, Aloka, Tokyo) and the emission of chemiluminescence was recorded.…”

“…The isolation of neutrophils was performed by the method described by Rosen and Klebanoff [16,18]. Briefly, a blood sample was drawn into a heparinized syringe (20 units/ ml of heparin) from the abdominal aorta following a laparotomy under lethal ether anesthesia.…”

“…To induce severe aseptic injury, burn injury was performed as previously described [13,16]. Briefly, under deep ether anesthesia, after shaving, the mice were placed in a plastic mold that exposes 20% of their total body surface area.…”

“…The isolation of Kupffer cells was performed as previously described [16,17]. Briefly, under deep ether anesthesia, the mice were sacrificed by bleeding, and then the livers were removed.…”