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Novel methylxanthine derivative-mediated anti-inflammatory effects in inflammatory bowel disease

World Journal of Gastroenterology 2014年第5期20卷 1127-1138页

作者： In-Ah Lee Alan Kamba Daren Low Emiko Mizoguchi Gastrointestinal Unit Department of Medicine Harvard Medical School Center for the Study of Inflammatory Bowel Disease Massachusetts General Hospital Harvard Medical School

Family 18 chitinases have a binding capacity with chitin, a polymer of N-acetylglucosamine. Recent studies strongly suggested that chitinase 3-like 1(CHI3L1, also known as YKL-40) and acidic mammalian chitinase, the two major members of family 18 chitinases, play a pivotal role in the pathogenesis of inflammatory bowel disease(IBD), bronchial asthma and several other inflammatory disorders. Based on the data from highthroughput screening, it has been found that three methylxanthine derivatives, caffeine, theophylline, and pentoxifylline, have competitive inhibitory effects against a fungal family 18 chitinase by specifically interacting with conserved tryptophans in the active site of this protein. Methylxanthine derivatives are also known as adenosine receptor antagonists, phosphodiesterase inhibitors and histone deacetylase inducers. Anti-in-flammatory effects of methylxanthine derivatives have been well-documented in the literature. For example, a beneficial link between coffee or caffeine consumption and type 2 diabetes as well as liver cirrhosis has been reported. Furthermore, theophylline has a long history of being used as a bronchodilator in asthma therapy, and pentoxifylline has an immuno-modulating effect for peripheral vascular disease. However, it is still largely unknown whether these methylxanthine derivativemediated anti-inflammatory effects are associated with the inhibition of CHI3L1-induced cytoplasmic signaling cascades in epithelial cells. In this review article we will examine the above possibility and summarize the biological significance of methylxanthine derivatives in intestinal epithelial cells. We hope that this study will provide a rationale for the development of methylxanthine derivatives, in particular caffeine,-based antiinflammatory therapeutics in the field of IBD and IBDassociated carcinogenesis.

关键词： Adherent-invasive Escherichia coli chitinase 3-like 1 chitinase inhibitors Intestinal epithelial cells Host-microbial interactions Inflammatory bowel disease

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