Immunomodulatory action of dietary fish oil and targeted deletion of intestinal epithelial cell PPARδ in inflammation-induced colon carcinogenesis

Am J Physiol Gastrointest Liver Physiol. 2012 Jan 1;302(1):G153-67. doi: 10.1152/ajpgi.00315.2011. Epub 2011 Sep 22.


The ligand-activated transcription factor peroxisome proliferator-activated receptor (PPAR)-δ is highly expressed in colonic epithelial cells; however, the role of PPARδ ligands, such as fatty acids, in mucosal inflammation and malignant transformation has not been clarified. Recent evidence suggests that the anti-inflammatory/chemoprotective properties of fish oil (FO)-derived n-3 polyunsaturated fatty acids (PUFAs) may be partly mediated by PPARδ. Therefore, we assessed the role of PPARδ in modulating the effects of dietary n-3 PUFAs by targeted deletion of intestinal epithelial cell PPARδ (PPARδ(ΔIEpC)). Subsequently, we documented changes in colon tumorigenesis and the inflammatory microenvironment, i.e., local [mesenteric lymph node (MLN)] and systemic (spleen) T cell activation. Animals were fed chemopromotive [corn oil (CO)] or chemoprotective (FO) diets during the induction of chronic inflammation/carcinogenesis. Tumor incidence was similar in control and PPARδ(ΔIEpC) mice. FO reduced mucosal injury, tumor incidence, colonic STAT3 activation, and inflammatory cytokine gene expression, independent of PPARδ genotype. CD8(+) T cell recruitment into MLNs was suppressed in PPARδ(ΔIEpC) mice. Similarly, FO reduced CD8(+) T cell numbers in the MLN. Dietary FO independently modulated MLN CD4(+) T cell activation status by decreasing CD44 expression. CD11a expression by MLN CD4(+) T cells was downregulated in PPARδ(ΔIEpC) mice. Lastly, splenic CD62L expression was downregulated in PPARδ(ΔIEpC) CD4(+) and CD8(+) T cells. These data demonstrate that expression of intestinal epithelial cell PPARδ does not influence azoxymethane/dextran sodium sulfate-induced colon tumor incidence. Moreover, we provide new evidence that dietary n-3 PUFAs attenuate intestinal inflammation in an intestinal epithelial cell PPARδ-independent manner.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / immunology
  • Animals
  • CD11a Antigen / biosynthesis
  • CD11a Antigen / immunology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Transformation, Neoplastic / drug effects*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology
  • Chronic Disease
  • Colitis / drug therapy*
  • Colitis / genetics
  • Colitis / immunology
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / immunology
  • Cytokines / biosynthesis
  • Dietary Fats, Unsaturated / immunology
  • Dietary Fats, Unsaturated / metabolism
  • Dietary Fats, Unsaturated / pharmacology*
  • Female
  • Fish Oils / immunology
  • Fish Oils / pharmacology*
  • Gene Deletion*
  • Hyaluronan Receptors / biosynthesis
  • Hyaluronan Receptors / immunology
  • Intestinal Mucosa / immunology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • PPAR delta / genetics
  • PPAR delta / immunology
  • PPAR delta / metabolism*
  • STAT3 Transcription Factor / biosynthesis
  • Spleen / drug effects
  • Spleen / immunology


  • CD11a Antigen
  • Cd44 protein, mouse
  • Cytokines
  • Dietary Fats, Unsaturated
  • Fish Oils
  • Hyaluronan Receptors
  • PPAR delta
  • STAT3 Transcription Factor
  • Stat3 protein, mouse