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PPARβ/δ Protects Against Experimental Colitis Through a Ligand-Independent Mechanism

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Abstract

Peroxisome proliferator-activated receptors (PPARs) β/δ and γ have overlapping roles in the negative regulation of inflammatory response genes. Ligand activation of PPARγ protects against experimental colitis in mice. PPARβ/δ can negatively regulate inflammation and is highly expressed in the epithelial cells of the colon, therefore PPARβ/δ may also have a role in experimental colitis. In these studies, colitis was induced by dextran sodium sulfate (DSS) treatment in wild-type and PPARβ/δ-null mice, with and without the PPARβ/δ specific ligand GW0742. PPARβ/δ-null mice exhibited increased sensitivity to DSS-induced colitis, as shown by marked differences in body weight loss, colon length, colonic morphology, myeloperoxidase activity and increased expression of mRNAs encoding the inflammatory markers interferon γ, tumor necrosis factor-α, and interleukin-6 compared to similarly treated wild-type mice. Interestingly, these differences were not affected by ligand activation of PPARβ/δ in either genotype. These studies demonstrate that PPARβ/δ expression in the colonic epithelium inhibits inflammation and protects against DSS-induced colitis through a ligand-independent mechanism.

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Acknowledgments

This work was supported by National Institutes of Health Grants CA97999 and CA89607 (to J.M.P.). The authors gratefully acknowledge Roberta Horner for providing technical support.

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Authors and Affiliations

  1. Department of Veterinary and Biomedical Sciences and The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, 312 Life Sciences Building, University Park, Pennsylvania, 16802, USA

    Holly E. Hollingshead, Mary J. Kennett & Jeffrey M. Peters

  2. Graduate Program in Biochemistry, Microbiology and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, 16802, USA

    Holly E. Hollingshead & Jeffrey M. Peters

  3. Laboratory of Metabolism, Center for Cancer Research, National Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Keiichirou Morimura, Masahiro Adachi & Frank J. Gonzalez

  4. Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709, USA

    Andrew N. Billin & Timothy M. Willson

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  1. Holly E. Hollingshead
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  2. Keiichirou Morimura
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  3. Masahiro Adachi
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  8. Jeffrey M. Peters
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Correspondence to Jeffrey M. Peters.

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Hollingshead, H.E., Morimura, K., Adachi, M. et al. PPARβ/δ Protects Against Experimental Colitis Through a Ligand-Independent Mechanism. Dig Dis Sci 52, 2912–2919 (2007). https://doi.org/10.1007/s10620-006-9644-9

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  • DOI: https://doi.org/10.1007/s10620-006-9644-9

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