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

Jennifer M. Monk, Wooki Kim, Evelyn Callaway, Harmony F. Turk, Jennifer E. Foreman, Jeffrey M. Peters, Weimin He, Brad Weeks, Robert C. Alaniz, David N. McMurray, Robert S. Chapkin

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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 (PPARδΔIEpC). 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 sulfateinduced colon tumor incidence. Moreover, we provide new evidence that dietary n-3 PUFAs attenuate intestinal inflammation in an intestinal epithelial cell PPARδ-independent manner.

Original languageEnglish (US)
Pages (from-to)G153-G167
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume302
Issue number1
DOIs
StatePublished - Jan 2012

All Science Journal Classification (ASJC) codes

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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