Involvement of interleukin-6 and tumor necrosis factor α in CYP3A11 and 2C29 down-regulation by Bacillus Calmette-Guerin and lipopolysaccharide in mouse liver

Bacillus Calmette-Guerin ( BCG) and lipopolysaccharide (LPS) are well known potent activators of the cell-mediated immune system and thus lead to the decreases in cytochrome P450 (P450). In this study we used interleukin (IL)-1alpha/beta, IL-6, or tumor necrosis factor alpha (TNFalpha) knockout (KO) mice to investigate how each cytokine is involved in P450 down-regulation, especially CYP3A11 and 2C29. BCG ( 40 mg/kg) was found to reduce both CYP3A11 and 2C29 mRNAs at 24 h after treatment in IL-1alpha/beta KO mice in a manner similar to that seen in wild-type mice. CYP3A11 mRNA, but not CYP2C29 mRNA, was significantly decreased by BCG treatment in the TNFalpha KO mice, although the decrease was less than that of wild-type or IL-1alpha/beta KO mice. In contrast, BCG showed no significant effect on CYP3A11 and 2C29 mRNAs in IL-6 KO mice. On the other hand, LPS was able to decrease CYP3A11 and 2C29 mRNA levels in all of the cytokine KO mice and markedly increased systemic levels of TNFalpha; BCG (40 mg/kg) lacked such activity. The present study has shown that IL-6 and TNFalpha are likely to be major factors involved in the down-regulation of CYP3A11 and 2C29 mRNAs in mice. In addition, there exist differences in the amount and/or kind of cytokines released by BCG or LPS, the latter being more potent than the former. This will be a possible reason for differential capability of P450 down-regulation between BCG and LPS.