Lipopolysaccharide (LPS) stimulates macrophages by activating NF-kappa B, which contributes to the release of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. 1,5-anhydro-D-fructose (1,5-AF) a monosaccha ride formed from starch and glycogen, exhibits anti-oxidant activity and enhances insulin secretion. This study examined the effects of 1,5-AF on LPS-induced inflammatory reactions and elucidated its molecular mechanisms. Before LPS challenge, mice were pretreated with 1,5-AF (38.5 mg/kg). We found that 1,5-AF pretreatment attenuated cytokine release into the serum, including TNF-alpha, IL-6 and macrophage chemoattractant protein (MCP)-1. Furthermore, pretreatment with 1,5-AF (500 mu g/ml) attenuated cytokine release, and 1,5-AF directly inhibited the nuclear translocalization of the NF-kappa B p65 subunit in LPS-stimulated murine macrophage-like RAW264.7 cells. This inhibition was responsible for decreased LPS-induced phosphorylation on Ser536 of the NF-kappa B p65 subunit, which is a posttranslational modification involved in the non-canonical pathway. Collectively, these findings indicate that the anti-inflammatory activity of 1,5-AF Occurs via inactivation of NF-kappa B. (C) 2009 Elsevier Inc. All rights reserved.