Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride.

UNLABELLED: Liver fibrosis is a common scarring response to all forms of chronic liver injury and is always associated with inflammation that contributes to fibrogenesis. Although a variety of cell populations infiltrate the liver during inflammation, it is generically clear that CD8 T lymphocytes promote while natural killer (NK) cells inhibit liver fibrosis. However, the role of invariant natural killer T (iNKT) cells, which are abundant in the liver, in hepatic fibrogenesis, remains obscure. Here we show that iNKT-deficient mice are more susceptible to carbon tetrachloride (CCl(4))-induced acute liver injury and inflammation. The protective effect of naturally activated iNKT in this model is likely mediated via suppression of the proinflammatory effect of activated hepatic stellate cells. Interestingly, strong activation of iNKT through injection of iNKT activator alpha-galactosylceramide (alpha-GalCer) accelerates CCl(4)-induced acute liver injury and fibrosis. In contrast, chronic CCl(4) administration induces a similar degree of liver injury in iNKT-deficient and wild-type mice, and only a slightly higher grade of liver fibrosis in iNKT-deficient mice than wild-type mice 2 weeks but not 4 weeks after CCl(4) injection, although iNKT cells are able to kill activated stellate cells. An insignificant role of iNKT in chronic liver injury and fibrosis may be attributable to hepatic iNKT cell depletion. Finally, chronic alpha-GalCer treatment had little effect on liver injury and fibrosis, which is attributable to iNKT tolerance after alpha-GalCer injection. CONCLUSION: Natural activation of hepatic iNKT cells inhibits, whereas strong activation of iNKT cells by alpha-GalCer accelerates CCl(4)-induced acute liver injury, inflammation, and fibrosis. During chronic liver injury, hepatic iNKT cells are depleted and play a role in inhibiting liver fibrosis in the early stage but not the late stage of fibrosis.

Carbon tetrachloride is immunosuppressive and decreases host resistance to Listeria monocytogenes and Streptococcus pneumoniae in female B6C3F1 mice.

Carbon tetrachloride (CCl(4)) is an environmental contaminant that has been detected in ambient air, seawater, surface-water and snow. The immunotoxic potential of CCl(4) was evaluated in female B6C3F1 mice. The animals were administered with CCl(4) daily for 14 days at doses of 50, 100, 500 or 1000 mg/kg body weight by gavage with corn oil as a vehicle. Exposure to CCl(4) resulted in an increase of liver weight but not the body weight and the weights of brain, spleen, lungs, thymus and kidneys. Exposure to CCl(4) produced minimal effect on differential hematological parameters; however, it produced a significant increase in serum glutamic-pyruvic transaminase (SGPT) levels in all dose groups while other serum chemistries showed sporadic increases, primarily at the dose level of 1000 mg/kg. Exposure to CCl(4) produced a decreased humoral immune response; the IgM antibody forming cell (AFC) response to sheep red blood cells (sRBC) was suppressed with the maximal decrease (45%) observed at the dose level of 1000 mg/kg. The IgM serum titer to sRBC was also reduced with a maximal decrease (54%) observed at the dose level of 500 mg/kg. Although exposure to CCl(4) had no effects on the mixed leukocyte response (MLR), cytotoxic T lymphocyte activity and natural killer (NK) cell activity, a decrease in both the absolute number and the percentage of CD4(+)CD8(-) at the dose level of 500 mg/kg was observed. The functional activity of the mononuclear phagocyte system was compromised as reflected by a decrease in the vascular clearance of (51)Cr-sRBC and a decrease in the uptake of (51)Cr-sRBC by the liver. Finally, in the two host resistance models evaluated, exposure to CCl(4) decreased host resistance to both Streptococcus pneumoniae and Listeria monocytogenes with greater susceptibility to the latter. Overall, these studies demonstrate that CCl(4) was immunosuppressive in female B6C3F1 mice.