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

Abstract

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 high-throughput 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-inflammatory 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 derivative-mediated 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 anti-inflammatory therapeutics in the field of IBD and IBD-associated carcinogenesis.

Keywords: Adherent-invasive Escherichia coli, Chitinase 3-like 1, Chitinase inhibitors, Intestinal epithelial cells, Host-microbial interactions, Inflammatory bowel disease

Core tip: The involvement of family 18 chitinases in the pathogenesis of inflammatory bowel disease has been increasing characterized. The discovery of methylxanthine derivatives as an effective inhibitor of family 18 chitinases provides a good tool to control the pathogenic effects of these proteins. This review discusses the underlying inhibitory mechanisms of the different methylxanthine derivatives and how these compounds have been shown to be effective in the amelioration of animal colitis models. As such, this mode of application can be extended to target other family 18 chitinases associated disorders such as asthma.