Rac Attack: Modulation of the Small GTPase Rac in Inflammatory Bowel Disease and Thiopurine Therapy.
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.
Department of Gastroenterology and Hepatology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands. ml.seinen@vumc.nl.
Margien L
ML
Seinen
Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands.
Geerten P
GP
van Nieuw Amerongen
Department of Gastroenterology and Hepatology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.
Nanne K H
NK
de Boer
Department of Gastroenterology and Hepatology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.|Department of Internal Medicine, Intensive Care and Internal Medicine (CO-MIK), Gastroenterology and Geriatrics, Zuyderland Medical Center, Heerlen-Sittard-Geleen, The Netherlands.
Adriaan A
AA
van Bodegraven
D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000235:genetics*; D015122:Mercaptopurine / Q000494:pharmacology*; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D005819:Genetic Markers; D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D019255:NADPH Oxidases; C527764:NCF2 protein, human; D020830:rac1 GTP-Binding Protein