Novel Guggulsterone Derivative GG-52 inhibits NF-kB Signaling in Intestinal Epithelial Cells and attenuates acute Murine Colitis

Abstract

BACKGROUND/AIM: The plant sterol guggulsterone has been reported to inhibit NF- B signaling in intestinal epithelial cells (IEC) and to ameliorate dextran sulfate sodium (DSS)-induced colitis in mice. The aim of this study was to investigate the anti-inflammatory effects of novel guggulsterone derivatives on IEC and preventive and therapeutic murine models of DSS-induced colitis. METHODS: Novel guggulsterone derivates with high lipophilicity were designed and four derivates, including GG-46, GG-50B, GG-52 and GG-53, were synthesized. COLO 205 colon epithelial cells were pre-treated with each derivative and then stimulated with TNF- . IL-8 expression was measured by real-time RT-PCR and ELISA. I B phosphorylation/ degradation was determined by immunoblotting and NF- B activity by electrophoretic mobility shift assay, and transcriptional reporter assay. Guggulsterone derivatives were administered to mice with preventive and therapeutic models of DSS-induced colitis. Colitis was quantified by body weight, disease activity index (DAI), colon length and histology. RESULTS: Two guggulsterone derivatives, GG-50B and GG-52, inhibited IL-8 expression, I B phosphorylation/degradation and NF- B activity in COLO 205 cells significantly. In preventive and therapeutic models of murine colitis, administration of GG-52 significantly reduced the severity of DSS-induced colitis, as assessed by DAI, colon length, and histology. In contrast, GG-50B did not show a significantly reduction in the colitis severity. Moreover, the efficacy on attenuating colitis by GG-52 was comparable to that by sulfasalazine or prednisolone. CONCLUSION: Guggulsterone derivative GG-52 blocks NF- B activation in IEC and ameliorates DSS-induced acute murine colitis, which suggesting that GG-52 is a potential therapeutic agent for the treatment of inflammatory bowel diseases. Key words: Guggulsterone derivatives, nuclear factor- B, inflammatory bowel disease, intestinal epithelial cells, murine colitis