Fenofibrate Represses Interleukin-17 and Interferon-γ Expression and Improves Colitis in Interleukin-10-Deficient Mice

Jimmy W. Lee, Poonam J. Bajwa, Monica J. Carson, Daniel R. Jeske, Yingzi Cong, Charles O. Elson, Christian Lytle, Daniel S. Straus

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Background & Aims: Interleukin-10 knockout (IL-10-/-) mice spontaneously develop colitis characterized by T-helper cell type 1-polarized inflammation. We tested the possible therapeutic activity of the peroxisome proliferator-activated receptor α (PPARα) ligand fenofibrate, and the PPARδ ligand GW0742, in IL-10-/- mice and investigated the cellular/molecular mechanisms for fenofibrate action. Methods: The effect of fenofibrate or GW0742 on the progression of colitis in C3H.IL-10-/- mice was evaluated. Effects of fenofibrate on cytokine and chemokine gene expression were studied in cultured splenocytes, pathogenic T cells isolated from C3H/HeJBir mice, and HT-29 colorectal cancer cells. Results: Treatment of C3H.IL-10-/- mice with fenofibrate delayed the onset of colitis, decreased the colonic histopathology score, and decreased colonic expression of genes encoding the inflammatory cytokines interferon-γ and interleukin (IL)-17. The target for fenofibrate, PPARα, was expressed in lymphocytes, macrophages, and crypt and surface epithelial cells of the colon. The mean number of lymphocytes was decreased by more than 75% in colonic sections of fenofibrate-treated as compared with control IL-10-/- mice, and fenofibrate repressed interferon-γ and IL-17 expression in isolated T cells. Fenofibrate also repressed the expression of the genes encoding 3 chemokines, CXCL10, CCL2, and CCL20, and repressed CXCL10 gene promoter activity in tumor necrosis factor-α-treated HT-29 cells. In contrast to the beneficial effect of fenofibrate, the PPARδ ligand GW0742 accelerated the onset of colitis in IL-10-/- mice. Conclusions: The immunopathology observed in IL-10-/- mice resembles that seen in Crohn's disease. The novel therapeutic activity of fenofibrate in this mouse model suggests that it may also have activity in Crohn's disease.

Original languageEnglish (US)
Pages (from-to)108-123
Number of pages16
JournalGastroenterology
Volume133
Issue number1
DOIs
StatePublished - Jun 2007
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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