Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth.
Although epidemiologic and experimental evidence strongly implicates chronic inflammation and dietary fats as risk factors for cancer, the mechanisms underlying their contribution to carcinogenesis are poorly understood. Here we present genetic evidence demonstrating that deletion of peroxisome proliferator-activated receptor δ (PPARδ) attenuates colonic inflammation and colitis-associated adenoma formation/growth. Importantly, PPARδ is required for dextran sodium sulfate induction of proinflammatory mediators, including chemokines, cytokines, COX-2, and prostaglandin E2 (PGE2), in vivo. We further show that activation of PPARδ induces COX-2 expression in colonic epithelial cells. COX-2-derived PGE2 stimulates macrophages to produce proinflammatory chemokines and cytokines that are responsible for recruitment of leukocytes from the circulation to local sites of inflammation. Our results suggest that PPARδ promotes colonic inflammation and colitis-associated tumor growth via the COX-2-derived PGE2 signaling axis that mediates cross-talk between tumor epithelial cells and macrophages.
Laboratory of Inflammation and Cancer, Biodesign Institute, and.
Dingzhi
D
Wang
Laboratory of Inflammation and Cancer, Biodesign Institute, and.
Lingchen
L
Fu
Department of Medicine, Vanderbilt Medical School, Nashville, TN 37232-2279;
Wei
W
Ning
Laboratory of Inflammation and Cancer, Biodesign Institute, and.
Lixia
L
Guo
Division of Reproductive Sciences, Cincinnati Children's Research Foundation, Cincinnati, OH 45229; and.
Xiaofei
X
Sun
Division of Reproductive Sciences, Cincinnati Children's Research Foundation, Cincinnati, OH 45229; and.
Sudhansu K
SK
Dey
Department of Medicine, Vanderbilt Medical School, Nashville, TN 37232-2279;
Rupesh
R
Chaturvedi
Department of Medicine, Vanderbilt Medical School, Nashville, TN 37232-2279;
Keith T
KT
Wilson
Laboratory of Inflammation and Cancer, Biodesign Institute, andDepartment of Chemistry and Biology, Arizona State University, Tempe, AZ 85287;Department of Research and Division of Gastroenterology, Mayo Clinic, Scottsdale, AZ 85259 duboisrn@asu.edu.
Raymond N
RN
DuBois
D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004041:Dietary Fats / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*
D004041:Dietary Fats; C091778:Ppard protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D016264:Dextran Sulfate; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone
COX-2/PGE2; colorectal cancer