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Author Notes:

Correspondence: Edward T. Morgan Department of Pharmacology Emory University, Atlanta, GA 30322 U.S.A; Email: etmorga@emory.edu; Tel: 404-727-5986; Fax: 404-727-0365

Acknowledgments: We are grateful to our colleagues Beatrice Nyagode for advice on cultured mouse hepatocytes; Daniel Kalman and Sara Lebeis for the IL1R−/− mice; and Malik Raynor for technical assistance.

Subjects:

Research Funding:

This work was supported by National Institutes of Health grants DK072372 and DK072372-S1 to ETM.

Keywords:

  • Cytochrome P450
  • Inflammation
  • Kupffer cells
  • Interleukin-1
  • TNFα

Selective Role for Tumor Necrosis Factor-?, but Not Interleukin-1 or Kupffer Cells, in Down-Regulation of CYP3A11 and CYP3A25 in Livers of Mice Infected with a Noninvasive Intestinal Pathogen

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Journal Title:

Biochemical Pharmacology

Volume:

Volume 82, Number 3

Publisher:

, Pages 312-321

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Hepatic cytochrome P450 (P450) gene and protein expression are modulated during inflammation and infection. Oral infection of C57BL/6 mice with Citrobacter rodentium produces mild clinical symptoms while selectively regulating hepatic P450 expression and elevating levels of proinflammatory cytokines. Here, we explored the role of cytokines in the regulation of hepatic P450 expression by orally infecting tumor necrosis factor-α (TNFα) receptor 1 null mice (TNFR1−/−), interleukin-1 (IL1) receptor null mice (IL1R−/−), and Kupffer cell depleted mice with C. rodentium. CYP4A mRNA and protein levels and flavin monooxygenase (FMO)3 mRNA expression levels were down-regulated, while CYP2D9 and CYP4F18 mRNAs remained elevated during infection in wild-type, receptor knockout, and Kupffer cell depleted mice. CYPs 3A11 and 3A25 mRNA levels were down-regulated during infection in wild-type mice but not in TNFR1−/− mice. Consistent with this observation, CYPs 3A11 and 3A25 were potently down-regulated in mouse hepatocytes treated with TNFα. Oral infection of IL1R−/− mice and studies with mouse hepatocytes indicated that IL1 does not directly regulate CYP3A11 or CYP3A25 expression. Uninfected mice injected with clodronate liposomes had a significantly reduced number of Kupffer cells in their livers. Infection increased the Kupffer cell count, which was attenuated by clodronate treatment. The P450 mRNA and cytokine levels in infected Kupffer cell depleted mice were comparable to those in infected mice receiving no clodronate. The results indicate that TNFα is involved in the regulation of CYPs 3A11 and 3A25, but IL1β and Kupffer cells may not be relevant to hepatic P450 regulation in oral C. rodentium infection.

Copyright information:

© 2011 Elsevier Inc. All rights reserved

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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