Targeting tumor necrosis factor (TNF)-α-mediated signal pathways may be a 
promising strategy for developing chemopreventive agents, because TNF-α-mediated 
cyclooxygenase (COX)-2 expression plays a key role in inflammation and 
carcinogenesis. Luteolin [2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-chromenone] 
exerts anticarcinogenic effects, although little is known about the underlying 
molecular mechanisms and specific targets of this compound. In the present 
study, we found that luteolin inhibited TNF-α-induced COX-2 expression by 
down-regulating the transactivation of nuclear factor-κB and activator 
protein-1. Furthermore, luteolin inhibited TNF-α-induced phosphorylation of 
mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) 
kinase 1/ERK/p90(RSK), mitogen-activated protein kinase kinase 4/c-Jun 
N-terminal kinase/c-Jun, and Akt/p70(S6K). However, it had no effect on the 
phosphorylation of p38. These effects of luteolin on TNF-α-mediated signaling 
pathways and COX-2 expression are similar to those achieved by blocking tumor 
progression locus 2 serine/threonine kinase (TPL2) using pharmacologic 
inhibitors and small interfering RNAs. Luteolin inhibited TPL2 activity in vitro 
and in TPL2 immunoprecipitation kinase assays by binding directly in an 
ATP-competitive manner. Overall, these results indicate that luteolin exerts 
potent chemopreventive activities, which primarily target TPL2.