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Peroxisome proliferator activated receptor γ in colonic epithelial cells protects against experimental inflammatory bowel disease
  1. M Adachi1,
  2. R Kurotani1,
  3. K Morimura1,
  4. Y Shah1,
  5. M Sanford2,
  6. B B Madison3,
  7. D L Gumucio3,
  8. H E Marin4,
  9. J M Peters4,
  10. H A Young2,
  11. F J Gonzalez1
  1. 1Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  2. 2Laboratory of Experimental Immunology, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
  3. 3Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA
  4. 4Department of Veterinary Science, Center for Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, PA, USA
  1. Correspondence to:
    Dr F J Gonzalez
    Building 37/Room 3106, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA; fjgonz{at}helix.nih.gov

Abstract

Introduction: Peroxisome proliferator activated receptor γ (PPARγ) is expressed in epithelial cells, macrophage, and T and B lymphocytes. Ligand induced activation of PPARγ was reported to attenuate colitis activity but it is not clear whether this protection is mediated by epithelial or leucocyte PPARγ.

Methods: Mice with targeted disruption of the PPARγ gene in intestinal epithelial cells, generated using a villin-Cre transgene and floxed PPARγ allele and designated PPARγΔIEpC, were compared with littermate mice having only the PPARγ floxed allele with no Cre transgene that expressed PPARγ in the gut, designated PPARγF/F. Colitis was induced by administering dextran sodium sulphate (DSS) and the two mouse lines compared for typical symptoms of disease and expression of inflammatory cytokines.

Results: PPARγΔIEpC mice displayed reduced expression of the PPARγ target genes ADRP and FABP in the gut but were otherwise normal. Increased susceptibility to DSS induced colitis, as defined by body weight loss, colon length, diarrhoea, bleeding score, and altered histology, was found in PPARγΔIEpC mice in comparison with PPARγF/F mice. Interleukin (IL)-6, IL-1β, and tumour necrosis factor α mRNA levels in colons of PPARγΔIEpC mice treated with DSS were higher than in similarly treated PPARγF/F mice. The PPARγ ligand rosiglitazone decreased the severity of DSS induced colitis and suppressed cytokine production in both PPARγF/F and PPARγΔIEpC mice.

Conclusions: These studies reveal that PPARγ expressed in the colonic epithelium has an endogenous role in protection against DSS induced colitis and that rosiglitazone may act through a PPARγ independent pathway to suppress inflammation.

  • ADRP, adipose differentiation related protein
  • DSS, dextran sodium sulphate
  • EpC, epithelial cell
  • FABP, fatty acid binding protein
  • F, floxed allele
  • IBD, inflammatory bowel disease
  • GAPDH, glyceraldehyde 3-phosphate dehydrogenase
  • KLF4, kruppel-like factor 4
  • PPAR, peroxisome proliferator activated receptor
  • TNF-α, tumour necrosis factor α
  • UC, ulcerative colitis
  • IL, interleukin
  • PCR, polymerase chain reaction
  • GAPDH, glyceraldehyde-3-phosphate dehydrogenase
  • RPA, ribonuclease protection assays
  • DIG, digoxigenin
  • MIF, macrophage migration inhibitory factor
  • peroxisome proliferator activated receptor γ
  • colitis
  • cytokines
  • inflammatory bile disease
  • rosiglitazone

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Footnotes

  • Published online first 17 March 2006

  • Conflict of interest: None declared.

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