Suppression of Lipopolysaccharide-Induced IL-1β Gene Expression by High-Molecular-Weight Adiponectin in RAW264.7 Macrophages.

Adiponectin is an abundant adipocytokine secreted by adipocytes. It exists in the plasma in its trimeric, hexameric, high-molecular-weight (HMW), and globular (a proteolytic product) isoforms. Adiponectin's anti-inflammatory effects on macrophages remain controversial. We have previously reported a simple and effective method for purifying native HMW adiponectin from human plasma. Here, we investigated whether native HMW adiponectin from human plasma has anti-inflammatory effects on macrophages. Pretreatment with human native HMW adiponectin inhibited lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β) gene expression, but not tumor necrosis factor (TNF)-α expression. However, simultaneous treatment with HMW adiponectin and LPS did not inhibit IL-1β expression. Further, HMW adiponectin pretreatment decreases glycogen synthase kinase-3β (GSK-3β) inactivation by abrogating LPS-induced Akt (Ser473) phosphorylation, which subsequently suppresses LPS-induced CCAAT/enhancer binding protein β (C/EBPβ) protein translation and nuclear translocation. However, HMW adiponectin pretreatment did not affect LPS-induced nuclear factor-kappaB (NF-κB) activation. These results suggest that HMW adiponectin mediates potent anti-inflammatory activities in macrophages by inhibiting its Akt-C/EBPβ signaling pathway, thereby suppressing IL-1β gene expression.