Digestive Diseases and Sciences

, Volume 57, Issue 10, pp 2580–2591

Soluble Epoxide Hydrolase Gene Deficiency or Inhibition Attenuates Chronic Active Inflammatory Bowel Disease in IL-10(−/−) Mice

  • Wanying Zhang
  • Allison L. Yang
  • Jie Liao
  • Haonan Li
  • Hua Dong
  • Yeon Tae Chung
  • Han Bai
  • Kristina A. Matkowskyj
  • Bruce D. Hammock
  • Guang-Yu Yang
Original Article

Abstract

Background

Soluble epoxide hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids (EETs) into their much less active dihydroxy derivatives dihydroxyeicosatrienoic acids. Thus, targeting sEH would be important for inflammation.

Aims

To determine whether knockout or inhibition of sEH would attenuate the development of inflammatory bowel disease (IBD) in a mouse model of IBD in IL-10(−/−) mice.

Methods

Either the small molecule sEH inhibitor trans/-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) or sEH knockout mice were used in combination with IL-10(−/−) mice. t-AUCB was administered to mice in drinking fluid. Extensive histopathologic, immunochemical, and biochemical analyses were performed to evaluate effect of sEH inhibition or deficiency on chronic active inflammation and related mechanism in the bowel.

Results

Compared to IL-10 (−/−) mice, sEH inhibition or sEH deficiency in IL-10(−/−) mice resulted in significantly lower incidence of active ulcer formation and transmural inflammation, along with a significant decrease in myeloperoxidase-labeled neutrophil infiltration in the inflamed bowel. The levels of IFN-γ, TNF-α, and MCP-1, as well VCAM-1 and NF-kB/IKK-α signals were significantly decreased as compared to control animals. Moreover, an eicosanoid profile analysis revealed a significant increase in the ratio of EETs/DHET and EpOME/DiOME, and a slightly down-regulation of inflammatory mediators LTB4 and 5-HETE.

Conclusion

These results indicate that sEH gene deficiency or inhibition reduces inflammatory activities in the IL-10 (−/−) mouse model of IBD, and that sEH inhibitor could be a highly potential in the treatment of IBD.

Keywords

Inflammatory bowel disease Soluble epoxide hydrolase Ephx2 gene IL-10 deficient mice Oxylipin profile 

Supplementary material

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Supplementary material 1 (DOC 25 kb)
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Supplementary material 2 (TIFF 1647 kb)
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Supplementary material 3 (DOC 49 kb)
10620_2012_2217_MOESM4_ESM.doc (44 kb)
Supplementary material 4 (DOC 44 kb)

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Wanying Zhang
    • 1
  • Allison L. Yang
    • 1
  • Jie Liao
    • 1
  • Haonan Li
    • 1
  • Hua Dong
    • 2
  • Yeon Tae Chung
    • 1
  • Han Bai
    • 1
  • Kristina A. Matkowskyj
    • 1
  • Bruce D. Hammock
    • 2
  • Guang-Yu Yang
    • 1
  1. 1.Department of PathologyFeinberg School of Medicine, Northwestern UniversityChicagoUSA
  2. 2.Department of EntomologyUniversity of CaliforniaDavisUSA

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