title: Immunomodulatory action of dietary fish oil and targeted deletion of intestinal epithelial cell PPARδ in inflammation-induced colon carcinogenesis.
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 (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.
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Texas A & M University, College Station, Texas 77843-2253, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Monk
authors.forename: Wooki
authors.initials: W
authors.lastname: Kim
authors.forename: Evelyn
authors.initials: E
authors.lastname: Callaway
authors.forename: Harmony F
authors.initials: HF
authors.lastname: Turk
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Foreman
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
authors.forename: Weimin
authors.initials: W
authors.lastname: He
authors.forename: Brad
authors.initials: B
authors.lastname: Weeks
authors.forename: Robert C
authors.initials: RC
authors.lastname: Alaniz
authors.forename: David N
authors.initials: DN
authors.lastname: McMurray
authors.forename: Robert S
authors.initials: RS
authors.lastname: Chapkin
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D000818:Animals; D040881:CD11a Antigen / Q000096:biosynthesis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D002908:Chronic Disease; D003092:Colitis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004042:Dietary Fats, Unsaturated / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005395:Fish Oils / Q000276:immunology / Q000494:pharmacology*; D017353:Gene Deletion; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047494:PPAR delta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D013154:Spleen / Q000187:drug effects / Q000276:immunology
chemical_list: D040881:CD11a Antigen; C476399:Cd44 protein, mouse; D016207:Cytokines; D004042:Dietary Fats, Unsaturated; D005395:Fish Oils; D018960:Hyaluronan Receptors; D047494:PPAR delta; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse