The guggulsterone derivative GG-52 inhibits NF-kappa B signaling in bone marrow-derived dendritic cells and attenuates colitis in IL-10 knockout mice

Abstract

Aims: We previously demonstrated that the novel guggulsterone derivative guggulsterone-52 (GG-52) inhibited the activation of nuclear factor (NF)-kappa B signaling in intestinal epithelial cells and had preventive and therapeutic effects on dextran sulfate sodium-induced acute colitis. This study investigates the anti-inflammatory effects of GG-52 on bone marrow-derived dendritic cells (BMDCs) and chronic colitis in IL-10(-/-) mice. Main methods: BMDCs were generated from the femurs of C57BL/6 wild-type and IL-10(-/-) mice. BMDCs were stimulated with lipopolysaccharide (LPS) in the presence or absence of GG-52. The effect of GG-52 on NF-kappa B signaling in BMDCs was examined by real-time RT-PCR for IL-12p40 and TNF-alpha gene expression, western blotting for I kappa B alpha degradation, and electrophoretic mobility shift assay. For in vivo studies, wildtype or IL-10(-/-) mice were treated with or without GG-52. Colitis was quantified by the evaluation of histopathological findings. Double immunofluorescence staining for CD11c and phosphorylated I kappa B kinase (IKK)-alpha was performed to detect IKK activation in DCs in colonic tissue. Key findings: GG-52 significantly inhibited LPS-induced IL-12p40 and TNF-alpha gene expression, I kappa B alpha degradation, and NF-kappa B DNA binding activity in BMDCs. In the IL-10(-/-) mouse model chronic colitis, administration of GG-52 significantly reduced the severity of colitis as assessed by histopathology, and suppressed IKK activation in DCs in colonic tissue. Significance: These results indicate that the novel guggulsterone derivative GG-52 blocks NF-kappa B activation in BMDCs and ameliorates chronic colitis in IL-10(-/-) mice, which suggest that GG-52 is a potential therapeutic agent for inflammatory bowel diseases. (C) 2013 Elsevier Inc. All rights reserved.