Abstract
In our previous study, a synthetic compound, (+)-(R,E)-6a1, that incorporated the key structures of anti-inflammatory algal metabolites and the endogenous peroxisome proliferator-activated receptor γ (PPAR-γ) ligand 15-deoxy-∆12,14-prostaglandin J2 (15d-PGJ2), exerted significant PPAR-γ transcriptional activity. Because PPAR-γ expressed in macrophages has been postulated as a negative regulator of inflammation, this study was designed to investigate the anti-inflammatory effect of the PPAR-γ agonist, (+)-(R,E)-6a1. Compound (+)-(R,E)-6a1 displayed in vitro anti-inflammatory activity in lipopolysaccharides (LPS)-stimulated murine RAW264.7 macrophages. Compound (+)-(R,E)-6a1 suppressed the expression of proinflammatory factors, such as nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), possibly by the inhibition of the nuclear factor-κB (NF-κB) pathway. In macrophages, (+)-(R,E)-6a1 suppressed LPS-induced phosphorylation of NF-κB, inhibitor of NF-κB α (IκBα), and IκB kinase (IKK). These results indicated that PPAR-γ agonist, (+)-(R,E)-6a1, exerts anti-inflammatory activity via inhibition of the NF-κB pathway.
Highlights
Peroxisome proliferator-activated receptor γ (PPAR-γ), which can be activated by natural or synthesized ligands, such as 15-deoxy-∆12,14 -prostaglandin J2 (15d-PGJ2 ) or rosiglitazone, respectively, is a member of the nuclear receptor superfamily [1]
Tissue damage, or exposure to endotoxin (i.e., lipopolysaccharides (LPS)), macrophages secrete a large amount of proinflammatory mediators, including inducible nitric oxide synthase, nitric oxide (NO), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6)
After ligand binding, the activated peroxisome proliferator-activated receptor γ (PPAR-γ) will translocate to the nucleus and bind to nuclear factor-κB (NF-κB) to repress the gene expression of proinflammatory mediators
Summary
Peroxisome proliferator-activated receptor γ (PPAR-γ), which can be activated by natural or synthesized ligands, such as 15-deoxy-∆12,14 -prostaglandin J2 (15d-PGJ2 ) or rosiglitazone, respectively, is a member of the nuclear receptor superfamily [1]. Activated PPAR-γ is translocated to the cell nucleus and forms a heterodimer with a second member of the nuclear receptor family, retinoic X receptor (RXR). Tissue damage, or exposure to endotoxin (i.e., lipopolysaccharides (LPS)), macrophages secrete a large amount of proinflammatory mediators, including inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6).
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