Modulation of Hepatic Cytochrome P450s by Citrobacter rodentium Infection in Interleukin-6-and Interferon-γ-Null Mice

After infection with Citrobacter rodentium, murine hepatic cytochrome P450 (P450) mRNAs are selectively regulated. Several serum proinflammatory cytokines are elevated, the most abundant being interleukin-6 (IL6). To elucidate the role of cytokines in the regulation of P450s during infection, we orally infected wild-type, IL6(-/-), or interferon-gamma(-/-) [IFN gamma(-/-)] female C57BL/6J mice with C. rodentium and analyzed hepatic P450 expression 7 days later. The majority of P450 mRNAs were equally affected by infection in each genotype, indicating that IL6 and IFN gamma are not the primary mediators of P450 downregulation in this disease model. The down-regulation of CYP3A11 and CYP3A13 and induction of CYP2D9 mRNAs were attenuated in the IL6(-/-) mice, suggesting a role of IL6 in the regulation of only these P450s. Similar evidence implicated IFN gamma in the regulation of CYP2D9, CYP2D22, CYP3A11, CYP3A25, and CYP4F18 mRNAs in C. rodentium infection and CYP2B9, CYP2D22, and CYP2E1 in the bacterial lipopolysaccharide model of inflammation. This is the first indication of an in vivo role for IFN gamma in hepatic P450 regulation in disease states. The deficiency of IL6 or IFN gamma affected serum levels of the other cytokines. Moreover, experiments in cultured hepatocytes demonstrated that tumor necrosis factor alpha (TNF alpha) is the most potent and efficacious of the cytokines tested in the regulation of murine P450 expression. It is therefore possible that part of the IFN gamma(-/-) and IL6(-/-) phenotypes could be attributed to the reduced levels of TNF alpha and part of the IFN gamma(-/-) phenotype could be caused by reduced levels of IL6.