Pycnogenol, an extract from French maritime pine, suppresses Toll-like receptor 4-mediated expression of adipose differentiation-related protein in macrophages

Abstract

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 (LPS) 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, whereas cycloheximide decreased the expression at 12 h, indicating that the LPS-induced ADRP expression was stimulated at the transcriptional level and was also mediated by new protein synthesis. LPS enhanced the ADRP promoter activity, in part, by stimulating activator protein (AP)-1 binding to the Ets/AP-1 element. In addition, preceding the increase of the ADRP mRNA, LPS induced the expression of interleukin (IL)-6, IL-1α, and interferon-β mRNAs, all of which stimulated the ADRP expression. Antibodies against these cytokines or inhibitors of c-Jun NH2-terminal kinase and nuclear factor (NF)-κB 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-κB, whereas 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.

Pine Bark Extracts: Nutraceutical, Pharmacological, and Toxicological Evaluation

“…Lipopolysaccharide upregulates ADRP transcription by first inducing the expression of IL-6, IL-1a, and interferon-b that subsequently stimulate ADRP expression (Gu et al, 2008). PYC suppresses the expression of ADRP and the aforementioned cytokines and may therefore be useful for the prevention of atherosclerosis.…”

Dynamics and regulation of lipid droplet formation in lipopolysaccharide (LPS)-stimulated microglia

“…Phosphorylation of p38 and JNK by upstream MAPK kinases leads to activation of transcription complex activator protein − 1 (AP-1), which then induces the expression of proinflammatory cytokines [26]. In LPS-treated macrophages, stimulation of the binding of AP-1 to the Ets/AP-1 binding site results in increased perilipin-2 expression [27]. Although the effect of LPS on perilipin-2 protein expression in macrophages has been previously examined [27,28], this has not been investigated in microglia.…”

“…In LPS-treated macrophages, stimulation of the binding of AP-1 to the Ets/AP-1 binding site results in increased perilipin-2 expression [27]. Although the effect of LPS on perilipin-2 protein expression in macrophages has been previously examined [27,28], this has not been investigated in microglia.…”

“…JNK activation leads to transcriptional activation of AP-1, a heterodimeric transcriptional complex [26]. It has been reported that LPS-induced perilipin-2 expression is in part mediated by an increased binding activity of AP-1 to the Ets/AP-1 element on the perilipin-2 gene promoter [27]. We first explored the effect of LPS on p38 and JNK by determining the extent of their phosphorylation by Western blot analysis.…”

Fatty acids regulate perilipin5 in muscle by activating PPARδ

“…7A, B ). To test the functionality of this element, we mutated the DR-1 element and performed reporter In addition to PPAR redundancy, the distinct regulation of Plin2 may also be infl uenced by other transcription factors ( 59,60 ). Several factors may infl uence recruitment of PPAR isoforms to a particular PPRE and subsequent transcriptional regulation.…”