Involvement of Smad7 in Inflammatory Diseases of the Gut and Colon Cancer.

Edoardo Troncone,Carmine Stolfi,Giovanni Monteleone,Irene Marafini

doi:10.3390/ijms22083922

Abstract

In physiological conditions, the human intestinal mucosa is massively infiltrated with various subsets of immune cells, the activity of which is tightly regulated by several counter-regulatory factors. One of these factors is transforming growth factor-β1 (TGF-β1), a cytokine produced by multiple cell types and targeting virtually all the intestinal mucosal cells. Binding of TGF-β1 to its receptors triggers Smad2/3 signaling, thus culminating in the attenuation/suppression of immune–inflammatory responses. In patients with Crohn’s disease and patients with ulcerative colitis, the major human inflammatory bowel diseases (IBD), and in mice with IBD-like colitis, there is defective TGF-β1/Smad signaling due to high levels of the intracellular inhibitor Smad7. Pharmacological inhibition of Smad7 restores TGF-β1 function, thereby reducing inflammatory pathways in patients with IBD and colitic mice. On the other hand, transgenic over-expression of Smad7 in T cells exacerbates colitis in various mouse models of IBD. Smad7 is also over-expressed in other inflammatory disorders of the gut, such as refractory celiac disease, necrotizing enterocolitis and cytomegalovirus-induced colitis, even though evidence is still scarce and mainly descriptive. Furthermore, Smad7 has been involved in colon carcinogenesis through complex and heterogeneous mechanisms, and Smad7 polymorphisms could influence cancer prognosis. In this article, we review the data about the expression and role of Smad7 in intestinal inflammation and cancer.

Highlights

The human intestine contains more immune cells than the rest of the body and this is because a myriad of dietary and microbial antigens continuously stimulate the intestinal immune system
Transforming Growth Factor (TGF)-β2 and TGF-β3 mainly play a role in bone development and muscle, while transforming growth factor-β1 (TGF-β1) is involved in the differentiation and functions of many immune cells, including T and B lymphocytes, NK cells and dendritic cells (DC) [11]
By assessing mucosal samples taken from patients with established Crohn’s disease (CD) and post-operative recurrence, we showed that induction of Smad7 occurs very early in the inflammatory cascade, which leads to the mucosal damage [29]

Summary

Introduction

The human intestine contains more immune cells than the rest of the body and this is because a myriad of dietary and microbial antigens continuously stimulate the intestinal immune system. Studies in animal models of immunity and inflammation indicate that reduced expression/function of such factors can break the immune tolerance towards the luminal microflora, thereby resulting in chronic colitis [2,4,5,6,7,8,9]. One such factor is Transforming Growth Factor (TGF)-β1, a component of the TGF-β superfamily [10]. TGF-β1 binds TβR2, leading to auto-phosphorylation of the receptor and subsequent recruitment of TβR1, with the formation of a transmembrane heterodimer. We here review the available evidence supporting the involvement of Smad in intestinal inflammation and colon cancer (CC)

Smad7 in Human IBD

Evidence Supporting the Pathogenic Role of Smad7 in the Gut

Smad7 in Other Inflammatory Pathologies of the Gut

Open Questions and Future Perspectives

Findings

Conclusions