Smad7 Sustains Inflammation in the Gut: From Bench to Bedside Irene Marafini, Silvia Sedda, Davide Di Fusco, Michele M Figliuzzi, Francesco Pallone and Giovanni Monteleone * Department of Systems Medicine, University of Rome Tor Vergata, Italy * Corresponding author: Giovanni Monteleone, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy, Tel: +39.06.72596158; Fax: +39.06.72596391; E-mail: Gi.Monteleone@Med.uniroma2.it Received date: April 29, 2014, Accepted date: July 09, 2014, Published date: July 16, 2014 Copyright: © 2014 Marafini I, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract In Crohn’s disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD) in human beings, the pathological process is driven by an excessive immune response that is directed against components of the luminal flora and inappropriately controlled by immunesuppressive mechanisms. One such a mechanism involves TGF-β1, a pleiotropic cytokine that targets both immune and non-immune cells in the gut. TGF- β1 is highly expressed in inflamed mucosa of IBD patients but paradoxically it is unable to activate Smad-associated intracellular signalling and suppress inflammatory cytokine responses. This is because IBD-related inflammation is marked by elevated levels of Smad7, an inhibitor of TGF-β1 signalling. Consistently, knockdown of Smad7 with a specific antisense oligonucleotide restores TGF-β1 function, inhibits inflammatory cytokine production, and ameliorates colitis in mice. In this article we review the available data supporting the pathogenic role of Smad7 in gut as well as the results of a recent phase 1 trial assessing the safety and tolerability of a Smad7 antisense oligonucleotide in CD patients. Keywords: Smad7; Gut; Inflammation Introduction Crohn’s disease (CD) and Ulcerative Colitis (UC) are the major chronic inflammatory bowel diseases (IBD) in humans. CD generally involves the terminal ileum and colon, but it can present anywhere in the alimentary tract, from the mouth to the anus, with inflammatory lesions that are often transmural and discontinuous. UC involves the rectum, and the inflammation typically confined to the mucosa or submucosal layers may extend proximally in a continuous pattern thus affecting part of the colon or the entire colon [1]. The aetiology of both CD and UC is unknown, but the rapid advancement of molecular techniques and the possibility to use several models of colitis have led to a better knowledge of mechanisms that orchestrate the tissue-destructive inflammatory response in these disorders. The most accredited hypothesis is that IBD result from the interaction between genetic and environmental factors that eventually leads to an exaggerated mucosal immune response directed against luminal bacteria [1-6]. This process seems to be facilitated, or at least perpetuated, by defects in counter-regulatory mechanisms. Indeed, mutations in genes encoding for the suppressive cytokine IL-10 or IL-10 receptor (R) are associated with paediatric forms of IBD characterized by early and aggressive course [7,8] and lack of IL-10 in mice favours the development of bacteria-driven colitis [9-11]. Along the same line is the demonstration that mice deficient in transforming growth factor (TGF)- β1, a pleiotropic cytokine with potent immunoregulatory properties, develop a multifocal immune- inflammatory disease, also involving the colon [12]. Gut inflammation can occur in transgenic mice that express a functionally inactive form of TGF-βR II on T cells and therefore are unable to respond to TGF-β1 [13]. Moreover, in murine models of colitis, neutralization of TGF-β1 leads to severe colitis while the presence of functional TGF-β1 is associated with either complete protection from the development of colitis or reduced severity of colitis [14,15]. Initial studies aimed at characterizing the expression of TGF-β1 in IBD showed elevated levels of RNA transcripts in inflamed mucosa of patients with CD and patients with UC as compared to uninflamed mucosal areas of the same patients and normal controls [16], thus excluding the possibility that defects in TGF-β1 production could contribute to sustain the IBD-related detrimental immune response. In contrast, a large body of evidence indicates that IBD are marked by disruption of TGF-β1 signalling due to elevated levels of the intracellular inhibitor, Smad7 [17]. In this article we review the data supporting the pathogenic role of Smad7 in gut and discuss the benefits and risks of the use of Smad7 inhibitors in CD patients. TGF-β1-Associated Smad Signalling in the Gut Within the gut mucosa of healthy individuals, several cell types [i.e. epithelial cells, macrophages, regulatory T cells (Tregs), myofibroblasts, and mast cells] can both produce and respond to TGF- β1 [12,18]. TGF-β1 is secreted as part of a latent complex, which includes latent TGF-β binding protein and latency-associated peptide (LAP), and in this form it cannot bind to its receptor [19]. TGF-β1 can be activated upon being released from the complex through the proteolytic action of a number of proteinases or upon the interaction between the tripeptide integrin-binding motif on LAP and the correspondent binding sequence on αvβ3, αvβ5, αvβ6 or αvβ8 integrins, expressed on the surface of epithelial cells, dendritic cells and myofibroblasts [20,21]. Active TGF-β1 binds the subunit II of its trans-membrane heterodimeric serine/threonine kinase receptor, thus promoting activation of subunit I, which in turns allows the phosphorylation and activation of the intra-cellular proteins Smad2 and Smad3 [22]. Once activated, Smad2 and Smad3 form a complex with Smad4 that eventually translocates to the nucleus where it regulates transcription of a wide spectrum of target genes (Figure 1) [22,23]. Several observations support the role of TGF-β1-associated Smad3 signalling in the maintenance of intestinal immune Marafini et al., J Clin Cell Immunol 2014, 5:4 DOI: 10.4172/2155-9899.1000236 Review Article Open Access J Clin Cell Immunol Inflammatory Bowel Disease ISSN:2155-9899 JCCI, an open access journal Journal of Clinical & Cellular Immunology J o u r n a l o f C l i n i c a l & C e ll u l a r I m m u n o l o g y ISSN: 2155-9899