Modulation of Hepatic Cytochrome P450s byCitrobacter rodentiumInfection in Interleukin-6- and Interferon-γ-Null Mice

Abstract

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(Ϫ/Ϫ), or interferon-␥(Ϫ/Ϫ) [IFN␥(Ϫ/Ϫ)] 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␥ 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(Ϫ/Ϫ) mice, suggesting a role of IL6 in the regulation of only these P450s. Similar evidence implicated IFN␥ 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␥ in hepatic P450 regulation in disease states. The deficiency of IL6 or IFN␥ affected serum levels of the other cytokines. Moreover, experiments in cultured hepatocytes demonstrated that tumor necrosis factor ␣ (TNF␣) 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␥(Ϫ/Ϫ) and IL6(Ϫ/Ϫ) phenotypes could be attributed to the reduced levels of TNF␣ and part of the IFN␥(Ϫ/Ϫ) phenotype could be caused by reduced levels of IL6.

Changes in expression of hepatic cytochrome P450 subfamily enzymes during development of adjuvant-induced arthritis in rats

“…Furthermore, inflammatory cytokines, such as TNF-α, IL-1, and IL-6, are well known to downregulate the gene expression of a wide variety of CYP 1-4 family enzymes (Morgan, 2001;Nyagode et al, 2010). …”

Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

“…This would suggest that IL-6 and IFN-g are not the only mediators of downregulation of P450 enzymes in this disease model (Nyagode et al, 2010). 4.…”

“…4. Mice with null mutations in cytokine or cytokine receptor genes display diminished down-regulation of cytochrome P450 in response to some inflammatory stimuli (Siewert et al, 2000;Ashino et al, 2004;Nyagode et al, 2010). 5.…”

CCN1 expression in hepatocytes contributes to macrophage infiltration in nonalcoholic fatty liver disease in mice

“…Primary murine hepatocytes were isolated from mice by in situ collagenase liver perfusion ( 14 ) and cultured in DMEM supplemented with 10% fetal bovine serum (FBS), 100 mg/ml streptomycin, and 100 U/ml penicillin (Invitrogen, Carlsbad, CA).…”