Abstract
Anti-tumor necrosis factor alpha (TNF-α) antibodies are effective in patients with inflammatory bowel disease (IBD). However, the effect is not optimal because a sufficient concentration of antibodies cannot be maintained at the site of inflammation. Thus, a macromolecular complex was developed with schizophyllan (SPG) and antisense oligonucleotides. In the present study, an SPG-antisense TNF-α complex was prepared, and its therapeutic efficacy was examined using a dextran sodium sulfate (DSS)-induced colitis model. The TNF-α production in CD11b+ macrophages significantly increased in the colon of DSS-treated mice. Dectin-1, a receptor of SPG, binds with SPG and is subsequently taken into the cells via phagocytosis. The expression of dectin-1 by CD11b+ macrophages significantly increased in DSS-treated mice. Flow cytometry revealed that the uptake of SPG-antisense TNF-α in the macrophages was efficient. TNF-α production was suppressed significantly by SPG-antisense TNF-α in vitro, which was administered via enema to evaluate its efficacy. The intrarectal administration of SPG-antisense TNF-α ameliorated the intestinal inflammation. In this study, we showed that the delivery system that conjugates SPG and antisense can have higher therapeutic efficacy. Thus, the new therapeutic approach presented in this study may be used in the management of IBD.
Highlights
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract
The expressions of TNF-α and other proinflammatory cytokines, such as interleukin (IL)-1β and IL-6, in the mucosa of dextran sodium sulfate (DSS)-treated mice were examined via real-time polymerase chain reaction (PCR)
Since the expression of TNF-α in the mucosa of DSS-treated mice increased, we examined the production of TNF-α in CD11b+ cells isolated from lamina propria (LP) cells
Summary
Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract. The pathogenesis of IBD is complex; the dysregulation of the intestinal immune system plays a key role in the development of the condition [2]. An increased level of TNF-α was detected in the mucosa of patients with IBD, and the intestinal inflammatory process shifted to Th1 during cytokine production [3,4]. Anti-tumor necrosis factor alpha (anti-TNF-α) antibodies (Abs) improved intestinal inflammation, indicating that they effectively increased cytokine production by Th1 cells in chronic inflammatory disease [5]. TNF-α has a pathogenic role as anti-TNF-α Abs significantly improved intestinal inflammation in IBD [6]. Ant-TNF-α Abs were widely used in patients with IBD
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