Adipose differentiation-related protein (ADRP) is highly expressed in macrophages and human atherosclerotic lesions. We demonstrated that Toll-like receptor (TLR) 4-mediated signals, which are involved in atherosclerosis formation, enhanced the expression of ADRP in macrophages. Lipopolysaccharide enhanced the ADRP expression in RAW264.7 cells or peritoneal macrophages from wild-type mice, but not in macrophages from TLR4-deficient mice. Actinomycin D almost completely abolished the LPS effect, while cycloheximide decreased the expression at 12 hr, indicating that the LPS-induced ADRP expression was stimulated at transcriptional level, and was also mediated by new protein synthesis. LPS enhanced the ADRP promoter activity, in part, by stimulating AP-1 binding to the Ets/AP-1 element. In addition, preceding the increase of the ADRP mRNA, LPS induced the expression of IL-6, IL-1, and IFN- mRNAs, all of which stimulated the ADRP expression. Antibodies against these cytokines or inhibitors of JNK and NF-B suppressed the ADRP mRNA level. Thus, TLR4 signals stimulate the ADRP expression both in direct and indirect manners. Pycnogenol (PYC), an extract of French maritime pine, suppressed the expression of ADRP and the above mentioned cytokines. PYC suppressed the ADRP promoter activity and enhancer activity of AP-1 and NF-B, while it did not affect the LPS-induced DNA binding of these factors. In conclusion, TLR4-mediated signals stimulate the ADRP expression in macrophages while PYC antagonizes this process. PYC, a widely used dietary supplement, might be useful for prevention of atherosclerosis.