The important role of MCP-1 during intestinal inflammation has been demonstrated in recent studies in which markedly increased MCP-1 level is observed in the colon tissue of IBD patients ( Reinecker et al., 1995).
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MCP-1 is considered to be one important chemokine regulating migration and infiltration of monocytes/macrophages. Chemokines, during inflammation, attract and activate leukocytes at the site of inflammation and up-regulate adhesion molecules that are important for leukocyte trafficking. Upon stimulation with TNF-α, disrupted epithelial cells in the intestinal mucosa perpetuate inflammatory process by secreting chemokines ( Eckmann et al., 1993 Schuerer-Maly et al., 1994 Jung et al., 1995). Therefore, there have been many efforts actively ongoing to identify an alternative and complimentary medicine regulating specific target molecules associated with IBD. Some patients develop side effects such as infusion reactions or infectious complications in addition to the high costs of this therapy ( Keane et al., 2001). However, there are some limitations in anti-TNF-α antibody therapy. Based on its pleiotropic pro-inflammatory nature, anti-TNF-α antibody has been developed for the treatment of IBD refractory to standard treatment with steroids ( Targan et al., 1997 Present et al., 1999). Such TNF-α-induced ROS leads to activation of the transcription factor, NF-κB, which is a major regulator of inflammatory gene expression ( Wajant et al., 2003). Upon stimulation with TNF-α, intestinal epithelium produces reactive oxygen species (ROS) through NAD(P)H oxidase (Nox) activation ( Kim et al., 2007 Babu et al., 2008). Early studies on IBD have shown that TNF-α expression is increased in blood ( Komatsu et al., 2001), intestinal mucosa ( Murch et al., 1993 Autschbach et al., 1995), stools ( Braegger et al., 1992), and cultured intestinal biopsies from IBD patients ( Reimund et al., 1996), suggesting that TNF-α plays a critical role in intestinal inflammation ( Murch et al., 1993). During recurrent inflammatory process, activated and infiltrated leukocytes produce pro-inflammatory cytokines, such as TNF-α. Inflammatory bowel disease (IBD) encompasses two chronic intestinal diseases, Crohn's disease (CD) and ulcerative colitis (UC), which are characterized by recurrent flare of inflammation in the gastrointestinal tract ( Podolsky, 2002 Elson et al., 2005). Taken together, the results strongly suggest GFW is a valuable medicinal food for IBD treatment, and thus may be used as an alternative medicine for IBD.
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The results suggest that GFW ameliorates colon inflammation by suppressing production of TNF-α as well as its signaling through NF-κB leading to the expression of inflammatory chemokines, MCP-1 and IL-8. Moreover, the effect of GFW was similar to that of intra-peritoneal injection of 5-aminosalicylic acid (5-ASA), an active metabolite of sulfasalazine, commonly used drug for the treatment of IBD. In an in vivo rat model of IBD, oral administration of GFW for 5 days (1 g/kg per day) significantly inhibited the trinitrobenzene sulfonic acid (TNBS)-induced weight loss, colon ulceration, myeloperoxidase activity, and TNF-α expression in the colon tissue. In differentiated U937 monocytic cells, LPS-induced TNF-α production, which is known to be mediated through NF-κB activation, was significantly suppressed by GFW. In addition, treatment with GFW significantly suppressed TNF-α-induced reactive oxygen species production and NF-κB transcriptional activity in HT-29 cells. The reduced adhesion by GFW correlated with the suppressed expression of MCP-1 and IL-8, the major IBD-associated chemokines. In coculture of HT-29 human colon cancer cells with U937 human monocytic cells, TNF-α-induced monocyte adhesion to HT-29 cells was significantly suppressed by GFW (10, 50, 100 µg/ml). In this study, water extract of Grifola frondosa (GFW) was evaluated for its protective effects against colon inflammation through the modulation of TNF-α action.
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TNF-α is a major cytokine involved in inflammatory bowel disease (IBD).