%0 Journal Article
%T Novel Pharmacological Approaches for Inflammatory Bowel Disease: Targeting Key Intracellular Pathways and the IL-23/IL-17 Axis
%A Leo R. Fitzpatrick
%J International Journal of Inflammation
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/389404
%X This review identifies possible pharmacological targets for inflammatory bowel disease (IBD) within the IL-23/IL-17 axis. Specifically, there are several targets within the IL-23/IL-17 pathways for potential pharmacological intervention with antibodies or small molecule inhibitors. These targets include TL1A (tumor necrosis factor-like molecule), DR3 (death receptor 3), IL-23, IL-17 and the receptors for IL-23 and IL-17. As related to IBD, there are also other novel pharmacological targets. These targets include inhibiting specific immunoproteasome subunits, blocking a key enzyme in sphingolipid metabolism (sphingosine kinase), and modulating NF-¦ÊB/STAT3 interactions. Several good approaches exist for pharmacological inhibition of key components in the IL-23 and IL-17 pathways. These approaches include specific monoclonal antibodies to TL1A, IL-17 receptor, Fc fusion proteins, specific antibodies to IL-17F, and small molecule inhibitors of IL-17 like Vidofludimus. Also, other potential approaches for targeted drug development in IBD include specific chemical inhibitors of SK, specific small molecule inhibitors directed against catalytic subunits of the immunoproteasome, and dual inhibitors of the STAT3 and NF-¦ÊB signal transduction systems. In the future, well-designed preclinical studies are still needed to determine which of these pharmacological approaches will provide drugs with the best efficacy and safety profiles for entrance into clinical trials. 1. Introduction During the past decade, there has been an expansion in new scientific knowledge related to the pathogenesis of inflammatory bowel disease (IBD). This knowledge has been summarized rather recently in published reviews, which provided key insights into IBD pathogenesis [1, 2]. Briefly, IBD consists of two distinct diseases, Crohn¡¯s disease (CD) and ulcerative colitis (UC). CD and UC are thought to arise due to a combination of genetic variations and alterations in the bacterial flora, which can subsequently drive a dysregulated immune response that results in chronic intestinal inflammation [1, 2]. Recent information related to the pathogenesis of IBD has provided the rationale for new pharmacological approaches to better treat the intestinal inflammation and related symptoms in patients. Another scientific review has succinctly summarized current therapies for IBD: mesalazine-based drugs, corticosteroids, immunosuppressive drugs (azathioprine/6-mercaptopurine, methotrexate, cyclosporin, anti-TNF agents), as well as emerging biologic agents such as antiadhesion and antiintegrin molecules
%U http://www.hindawi.com/journals/iji/2012/389404/