Effect of PPAR activators on cytokine-stimulated cyclooxygenase-2 expression in human colorectal carcinoma cells

Cyclooxygenase-2 (COX-2) expression is up-regulated in colorectal cancer ti ssue. Peroxisome proliferator-activated receptors (PPARs) are expressed in human colorectal tissue and activation of PPARs can alter COX-2 expression. In macrophages, activation of PPARs down-regulates COX-2 expression. We ex amined the effect of PPAR alpha and PPAR gamma ligands on untreated and TNF -alpha -induced COX-2 expression in the human colorectal epithelial cell li ne HT-29. The expression of PPAR alpha and PPAR gamma was confirmed in thes e cells. TNF-alpha, an inflammatory cytokine, increased COX-2 expression vi a the NF kappaB pathway. In the absence of TNF-alpha, WY14643 (PPAR alpha a ctivator) caused an increase, while BRL49653 (PPAR gamma activator) did not alter COX-2 expression. When HT-29 cells were incubated with TNF-alpha and WY14643, a further increase in COX-2 expression was detected, Incubation w ith TNF-alpha and BRL49653 caused an additional twofold increase in COX-2 e xpression. Our results suggest that both PPAR alpha signaling and TNF-alpha signaling increase COX-2 expression by independent pathways, while PPAR ga mma stimulates COX-2 expression by up-regulation of the TNF-alpha pathway.