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

84 Citations (Scopus)

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

Fingerprint

Fenofibrate
Interleukin-17
Colitis
Interleukin-10
Interferons
Peroxisome Proliferator-Activated Receptors
Ligands
Gene Expression
Crohn Disease
Chemokine CCL20
Chemokine CXCL10
Cytokines
T-Lymphocytes
HT29 Cells
Th1 Cells
Inbred C3H Mouse
Chemokine CCL2
Lymphocyte Count
Chemokines
Colorectal Neoplasms

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Fenofibrate Represses Interleukin-17 and Interferon-γ Expression and Improves Colitis in Interleukin-10-Deficient Mice. / Lee, Jimmy W.; Bajwa, Poonam J.; Carson, Monica J.; Jeske, Daniel R.; Cong, Yingzi; Elson, Charles O.; Lytle, Christian; Straus, Daniel S.

In: Gastroenterology, Vol. 133, No. 1, 06.2007, p. 108-123.

Research output: Contribution to journalArticle

Lee, Jimmy W. ; Bajwa, Poonam J. ; Carson, Monica J. ; Jeske, Daniel R. ; Cong, Yingzi ; Elson, Charles O. ; Lytle, Christian ; Straus, Daniel S. / Fenofibrate Represses Interleukin-17 and Interferon-γ Expression and Improves Colitis in Interleukin-10-Deficient Mice. In: Gastroenterology. 2007 ; Vol. 133, No. 1. pp. 108-123.
@article{c021137b9e104c25af5ef1ee8dc157c7,
title = "Fenofibrate Represses Interleukin-17 and Interferon-γ Expression and Improves Colitis in Interleukin-10-Deficient Mice",
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.",
author = "Lee, {Jimmy W.} and Bajwa, {Poonam J.} and Carson, {Monica J.} and Jeske, {Daniel R.} and Yingzi Cong and Elson, {Charles O.} and Christian Lytle and Straus, {Daniel S.}",
year = "2007",
month = "6",
doi = "10.1053/j.gastro.2007.03.113",
language = "English (US)",
volume = "133",
pages = "108--123",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "1",

}

TY - JOUR

T1 - Fenofibrate Represses Interleukin-17 and Interferon-γ Expression and Improves Colitis in Interleukin-10-Deficient Mice

AU - Lee, Jimmy W.

AU - Bajwa, Poonam J.

AU - Carson, Monica J.

AU - Jeske, Daniel R.

AU - Cong, Yingzi

AU - Elson, Charles O.

AU - Lytle, Christian

AU - Straus, Daniel S.

PY - 2007/6

Y1 - 2007/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=34447101284&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34447101284&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2007.03.113

DO - 10.1053/j.gastro.2007.03.113

M3 - Article

C2 - 17631136

AN - SCOPUS:34447101284

VL - 133

SP - 108

EP - 123

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 1

ER -