Fenofibrate represses interleukin-17 and interferon-gamma expression and improves colitis in interleukin-10-deficient mice.
OBJECTIVE
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 alpha (PPARalpha) ligand fenofibrate, and the PPARdelta 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-gamma and interleukin (IL)-17. The target for fenofibrate, PPARalpha, 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-gamma 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-alpha-treated HT-29 cells. In contrast to the beneficial effect of fenofibrate, the PPARdelta 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.
Lee
Jimmy W
JW
Biomedical Sciences Division, University of California, Riverside, California 92521-0121, USA.
Bajwa
Poonam J
PJ
Carson
Monica J
MJ
Jeske
Daniel R
DR
Cong
Yingzi
Y
Elson
Charles O
CO
Lytle
Christian
C
Straus
Daniel S
DS
D000367:Age Factors; D000818:Animals; D002452:Cell Count; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D003424:Crohn Disease / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D011345:Fenofibrate / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D019073:HT29 Cells; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics*; D020381:Interleukin-17 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D047493:PPAR alpha / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D010636:Phenols; D013438:Sulfhydryl Compounds
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D011345:Fenofibrate; D000960:Hypolipidemic Agents; D007371:Interferon-gamma; D016753:Interleukin-10; D020381:Interleukin-17; D047493:PPAR alpha; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds