Peroxisome proliferator-activated receptor ä 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 ä (PPARä) attenuates colonic inflammation and colitis-associated adenoma formation/growth. Importantly, PPARä is required for dextran sodium sulfate induction of proinflammatory mediators, including chemokines, cytokines, COX-2, and prostaglandin E ₂ (PGE2), in vivo. We further show that activation of PPARä induces COX-2 expression in colonic epithelial cells. COX-2-derived PGE ₂ 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 PPARä 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.