Enterotoxigenic Bacteroides fragilis (ETBF) produces an approximately 20-kDa heat-labile enterotoxin (BFT) that plays an essential role in mucosal inflammation. Although spontaneous disappearance of ETBF infection is common, little information is available on regulated expression of antibacterial factors in response to BFT stimulation. This study investigates the role of BFT in human β-defensin 2 (hBD-2) induction from intestinal epithelial cells. Stimulation of HT-29 and Caco-2 intestinal epithelial cell lines with BFT resulted in the induction of hBD-2. Activation of a reporter gene for hBD-2 was dependent on the presence of NF-κB binding sites. In contrast, suppression of AP-1 did not affect hBD-2 expression in BFT-stimulated cells. Inhibition of p38 mitogen-activated protein kinase (MAPK) using SB203580 and small interfering RNA (siRNA) transfection resulted in a significant reduction in BFT-induced IκB kinase (IKK)/NF-κB activation and hBD-2 expression. Our results suggest that a pathway including p38 MAPK, IKK, and NF-κB activation is required for hBD-2 induction in intestinal epithelial cells exposed to BFT, and may be involved in the host defense following infection with ETBF.
We already showed that the plant sterol guggulsterone has been reported to inhibit nuclear factor-kB (NF-kB) signaling in intestinal epithelial cells (IECs) and to attenuate dextran sulfate sodium (DSS)-induced colitis. This study investigates the anti-inflammatory effects of novel guggulsterone derivatives on IEC and preventive and therapeutic murine models of DSS-induced colitis. Novel guggulsterone derivates with high lipophilicity were designed and four derivates, including GG-46, GG-50B, GG-52, and GG-53, were synthesized. Two guggulsterone derivatives, GG-50B and GG-52, significantly inhibited the activated NF-kB signals and the upregulated expression of interleukin-8 (IL-8) in COLO 205 cells stimulated with tumor necrosis factor-a (TNF-a). Pretreatment with GG-50B and GG-52 attenuated the increased IkB kinase (IKK) and IkBa phsophorylation induced by TNF-a. In preventive and therapeutic models of murine colitis, administration of GG-52 significantly reduced the severity of DSS-induced colitis, as assessed by disease activity index, colon length, and histology. In contrast, GG-50B did not show a significant reduction in the colitis severity. Moreover, the efficacy on attenuating colitis by GG-52 was comparable to that by sulfasalazine or prednisolone. These results indicate that the novel guggulsterone derivative GG-52 blocks NF-kB activation in IEC and ameliorates DSS-induced acute murine colitis, which suggests that GG-52 is a potential therapeutic agent for the treatment of inflammatory bowel diseases.
DA‐6034 is a synthetic derivative of eupatilin, a flavonoid with anti‐inflammatory effects. The aim of this study was to investigate the effects of DA‐6034 on the interactions between IκB kinase (IKK) and heat shock protein 90 (Hsp90), and activation of the nuclear factor‐kappaB (NF‐κB) signalling pathway in human gastric epithelial cells infected with Helicobacter pylori. MKN‐45 gastric epithelial cell line was treated with DA‐6034 and H. pylori. DA‐6034 significantly inhibited NF‐κB activation and upregulated the expressions of interleukin‐8 (IL‐8) and monocyte chemoattractant protein‐1 in MKN‐45 cells infected with H. pylori. However, DA‐6034 did not influence activator protein‐1 DNA binding activity in H. pylori‐infected gastric epithelial cells. Pretreatment with DA‐6034 attenuated the H. pylori‐induced increase in IKK activity, and Hsp90 was associated with IKK‐α and IKK‐γ in MKN‐45 cells. Treatment with DA‐6034 dissociated the Hsp90 and IKK‐γ complex in H. pylori‐infected cells, leading to the inhibition of IL‐8 expression. These results suggest that the eupatilin derivative 7‐carboxymethyloxy‐3′,4′,5‐trimethoxy flavone has anti‐inflammatory activity in gastric epithelial cells infected with H. pylori through the promotion of the dissociation of the IKK‐γ–Hsp90 complex and suppression of NF‐κB signalling.
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