<jats:p> <jats:list list-type="explicit-label"> <jats:list-item><jats:p>Ethyl caffeate, a natural phenolic compound, was isolated from <jats:italic>Bidens pilosa</jats:italic>, a medicinal plant popularly used for treating certain inflammatory syndromes. The purpose of this study was to investigate the structural activity, and the anti‐inflammatory functions and mechanism(s) of ethyl caffeate.</jats:list-item> <jats:list-item><jats:p>Ethyl caffeate was found to markedly suppress the lipopolysaccharide (LPS)‐induced nitric oxide (NO) production (IC<jats:sub>50</jats:sub>=5.5 <jats:italic>μ</jats:italic>g ml<jats:sup>−1</jats:sup>), mRNA and protein expressions of inducible nitric oxide synthase (iNOS), and prostaglandin E<jats:sub>2</jats:sub> (PGE<jats:sub>2</jats:sub>) production in RAW 264.7 macrophages.</jats:list-item> <jats:list-item><jats:p>Transient gene expression assays using human <jats:italic>cox‐2</jats:italic> promoter construct revealed that ethyl caffeate exerted an inhibitory effect on <jats:italic>cox‐2</jats:italic> transcriptional activity in 12‐<jats:italic>O</jats:italic>‐tetradecanoylphorbol‐13‐acetate (TPA)‐treated MCF‐7 cells.</jats:list-item> <jats:list-item><jats:p>Immunohistochemical studies of mouse skin demonstrated that TPA‐induced COX‐2 expression was significantly inhibited by ethyl caffeate with a superior effect to that of celecoxib, a nonsteroidal anti‐inflammatory drug.</jats:list-item> <jats:list-item><jats:p>The phosphorylation and degradation of inhibitor <jats:italic>κ</jats:italic>B (I<jats:italic>κ</jats:italic>B) and the translocation of nuclear transcription factor‐<jats:italic>κ</jats:italic>B (NF‐<jats:italic>κ</jats:italic>B) into the nucleus, as well as the activation of mitogen‐activated protein kinases (MAPKs) induced by LPS in macrophages, were not affected by ethyl caffeate. Ethyl caffeate, however, could inhibit NF‐<jats:italic>κ</jats:italic>B activation by impairing the binding of NF‐<jats:italic>κ</jats:italic>B to its <jats:italic>cis</jats:italic>‐acting element. These results suggest that ethyl caffeate suppresses iNOS and COX‐2 expressions partly through the inhibition of the NF‐<jats:italic>κ</jats:italic>B·DNA complex formation.</jats:list-item> <jats:list-item><jats:p>Structure–activity relationship analyses suggested that the catechol moiety and <jats:italic>α,β</jats:italic>‐unsaturated ester group in ethyl caffeate are important and essential structural features for preventing NF‐<jats:italic>κ</jats:italic>B·DNA complex formation. This study provides an insight into the probable mechanism(s) underlying the anti‐inflammatory and therapeutic properties of ethyl caffeate.</jats:list-item> </jats:list> <jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2005) <jats:bold>146</jats:bold>, 352–363. doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/sj.bjp.0706343">10.1038/sj.bjp.0706343</jats:ext-link>