These results indicate that metformin suppresses NF-κB activation in intestinal epithelial cells and ameliorates murine colitis and colitis-associated tumorigenesis in mice, suggesting that metformin could be a potential therapeutic agent for the treatment of inflammatory bowel disease.

Enterotoxigenic Bacteroides fragilis (ETBF) is associated with noninvasive diarrheal diseases (1, 2), inflammatory bowel diseases (1), and colorectal cancers (3-5). B. fragilis enterotoxin (BFT), a virulence factor of ETBF, is responsible for these diseases (1). BFT interacts with a single layer of intestinal epithelial cells and can provoke signals that induce mucosal inflammation (1, 6-9).In mammalian cells, two genetically distinct isozymes of heme oxygenase (HO) have been clearly identified. HO-1 is inducible, whereas HO-2 is constitutively expressed. HO-1 catalyzes the degradation of free heme into carbon monoxide, biliverdin, and free iron (10, 11). Within mammalian cells, biliverdin reductase converts biliverdin to bilirubin. Pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), lipoteichoic acid, and peptidoglycan, as well as several proinflammatory cytokines, can induce HO-1 expression (12). Upregulated HO-1 expression can lead to adaptive immune responses that protect cells from immunopathogenesis or stress damage (12, 13). In addition, HO-1 expression is involved in clearance of pathogenic bacteria and downregulation of inflammatory responses. For example, HO-1 deficiency not only results in inadequate pathogen clearance (14) but also promotes the development of necrotizing enterocolitis-like intestinal injury in mice (15). HO-1 and HO-1-induced carbon monoxide can ameliorate intestinal inflammation through promotion of bacterial clearance (16). The HO-1/carbon monoxide pathway also suppresses Toll-like receptor 4 (TLR4) signaling, leading to downregulation of proinflammatory signaling induced by stimulation with LPS (17). Based on these findings, we hypothesized that the induction of HO-1 may regulate inflammatory responses induced by BFT. However, there are no reports regarding BFT-induced HO-1 expression.Signals from transcription factors, including nuclear factor-B (NF-B), activator protein-1 (AP-1), and NF-E2-related factor 2 (Nrf2, or nuclear factor [erythroid-derived 2]-like 2 [NFE2L2]), regulate the expression of HO-1 (11). Stimulation of intestinal epithelial cells with BFT can activate NF-B and AP-1 signaling (6)(7)(8)(9)(18)(19)(20). We have previously demonstrated that exposure of intestinal epithelial cells to BFT results in delayed apoptosis, suggesting that protection of cells after BFT stimulation is related to the generation of signals that activate or suppress mucosal inflammation (21). These observations raise the possibility that signaling molecules that regulate HO-1 expression may be activated in BFTexposed cells. However, there is no evidence that BFT-induced signaling results in HO-1 induction in intestinal epithelial cells. We therefore investigated HO-1 induction in response to stimulation of intestinal epithelial cells with BFT. We found that a signaling pathway involving p38 mitogen-activated protein kinases (MAPKs)-IB kinase (IKK)-NF-B in intestinal epithelial cells is required for HO-1 induction following exposure to BFT.

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Summary 5,7-Dihydroxy-3′,4′,6′-trimethoxyflavone (eupatilin), the active pharmacological ingredient from Artemisia asiatica Nakai (Asteraceae), is reported to have a variety of anti-inflammatory properties in intestinal epithelial cells. However, little information is known about the molecular mechanism of eupatilin-induced attenuation of bronchial epithelial inflammation. This study investigates the role of eupatilin in the adhesion of inflammatory cells such as monocytes and eosinophils to bronchial epithelial cells. Stimulation of a human bronchial epithelial cell line (BEAS-2B) with tumour necrosis factor-a (TNF-a) increased the expression of surface adhesion molecules, including intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), in which eupatilin significantly inhibited the expression of those adhesion molecules in a dose-dependent manner. Eupatilin suppressed the TNF-a-induced activation of IjBa and nuclear factor-jB (NF-jB) signals in BEAS-2B cells. The IjB kinase (IKK) activation was also significantly reduced in eupatilin-pre-treated BEAS-2B and primary normal human bronchial epithelial (NHBE) cells. However, eupatilin did not influence AP-1 activity in TNF-a-stimulated cells. Suppression of NF-jB signalling induced by eupatilin resulted in the inhibition of the expression of adhesion molecules and the adhesion of monocytes and eosinophils to BEAS-2B cells. Furthermore, eupatilin suppressed the phosphorylation of Akt in TNF-a-stimulated BEAS-2B and NHBE cells, leading to down-regulation of NF-jB activation and adhesion molecule expression and finally to suppression of the inflammatory cell adhesion to epithelial cells. These results suggest that eupatilin can inhibit the adhesion of inflammatory cells to bronchial epithelial cells via a signalling pathway, including activation of Akt and NF-jB, as well as expression of adhesion molecules.

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