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

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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.

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Acknowledgments

This study was supported by NIH R01 CA137467 to GYY. Partial supports were provided by NIEHS R01 ES002710 and NIEHS Superfund Program P42 ES004699. BDH is a George and Judy Marcus Senior Fellow of The American Asthma Foundation.

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None.

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Authors and Affiliations

  1. Department of Pathology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL, 60611, USA

    Wanying Zhang, Allison L. Yang, Jie Liao, Haonan Li, Yeon Tae Chung, Han Bai, Kristina A. Matkowskyj & Guang-Yu Yang

  2. Department of Entomology, University of California, One Shields Avenue, Davis, CA, 95616, USA

    Hua Dong & Bruce D. Hammock

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  1. Wanying Zhang
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  2. Allison L. Yang
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  10. Guang-Yu Yang
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Correspondence to Guang-Yu Yang.

Additional information

Wanying Zhang and Allison L. Yang contributed equally to this work.

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Zhang, W., Yang, A.L., Liao, J. et al. Soluble Epoxide Hydrolase Gene Deficiency or Inhibition Attenuates Chronic Active Inflammatory Bowel Disease in IL-10(−/−) Mice. Dig Dis Sci 57, 2580–2591 (2012). https://doi.org/10.1007/s10620-012-2217-1

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