Rac Attack: Modulation of the Small GTPase Rac in Inflammatory Bowel Disease and Thiopurine Therapy
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REVIEW ARTICLE
Rac Attack: Modulation of the Small GTPase Rac in Inflammatory Bowel Disease and Thiopurine Therapy Margien L. Seinen1 • Geerten P. van Nieuw Amerongen2 • Nanne K. H. de Boer1 Adriaan A. van Bodegraven1,3
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Ó The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract The incidence and prevalence of inflammatory bowel disease (IBD) are increasing. Although the etiology of IBD is unknown, it is thought that genetically susceptible individuals display an inappropriate inflammatory response to commensal microbes, resulting in intestinal tissue damage. Key proteins involved in regulating the immune response, and thus in inflammation, are the small triphosphate-binding protein Rac and its regulatory network. Recent data suggest these proteins to be involved in (dys)regulation of the characteristic inflammatory processes in IBD. Moreover, Rac-gene variants have been identified as susceptibility risk factors for IBD, and Rac1 GTPase signaling has been shown to be strongly suppressed in non-inflamed mucosa compared with inflamed colonic mucosa in IBD. In addition, first-line immunosuppressive treatment for IBD includes thiopurine therapy, and its immunosuppressive effect is primarily ascribed to Rac1 suppression. In this review, we focus on Rac modification and its potential role in the development of IBD, Rac as the molecular therapeutic target in current thiopurine therapy, and the modulation of the Rac signal transduction pathway as a promising novel therapeutic strategy. & Margien L. Seinen [email protected] 1
Department of Gastroenterology and Hepatology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
2
Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands
3
Department of Internal Medicine, Intensive Care and Internal Medicine (CO-MIK), Gastroenterology and Geriatrics, Zuyderland Medical Center, Heerlen-Sittard-Geleen, The Netherlands
Key Points Genetic variants of Rac1 and NCF2 are identified as susceptibility single nucleotide polymorphisms for IBD. The immunosuppressive mechanism of thiopurine treatment relies on the modification of Rac1. Rac1 may serve as a potential biomarker to predict (pharmacological) effectiveness of thiopurine therapy.
1 Introduction Inflammatory bowel disease (IBD), with its two main entities Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the gastrointestinal tract and causes a significant disease burden, and the incidence is rising globally [1]. Although the etiology of IBD is yet unknown, it is thought that IBD results from an inappropriate inflammatory reaction to commensal microbes in genetically susceptible individuals [2]. In genetic association studies, several gene variants and genetic risk loci, crucial for intestinal homeostasis and affecting the immune response, which contribute to the development of (or protection against) IBD have been identified [3]. This inappropriate inflammatory response to commensal microbes re
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