Abstract
The human gastrointestinal tract contains the largest population of immune cells in the body and this is a reflection of the fact that it is continuously exposed to a myriad of dietary and bacterial antigens. Although these cells produce a variety of inflammatory cytokines that could potentially promote tissue damage, in normal conditions the mucosal immune response is tightly controlled by counter-regulatory factors, which help induce and maintain gut homeostasis and tolerance. One such factor is transforming growth factor (TGF)-β1, a cytokine produced by multiple lineages of leukocytes, stromal cells and epithelial cells, and virtually targets all the gut mucosal cell types. Indeed, studies in animals and humans have shown that defects in TGF-β1 production and/or signaling can lead to the development of immune-inflammatory pathologies, fibrosis and cancer in the gut. Here, we review and discuss the available evidence about the role of TGF-β1 and Smad7, an inhibitor of TGF-β1 activity, in gut inflammation, fibrosis and cancer with particular regard to the contribution of these two molecules in the pathogenesis of inflammatory bowel diseases and colon cancer.
Highlights
The human gastrointestinal (GI) tract harbors the largest population of immune cells in the body and this is the result of a continuous exposure of the gut immune system to a complex and dynamic population of microorganisms and dietary antigens [1]
The intestinal lamina propria (LP) is a loosely organized lymphoid compartment regarded as the major effector site for intestinal immune responses, with various kinds of immune cells communicating with one another through cell-cell contact and/or cytokine production [14]
The fibrogenic role of transforming growth factor (TGF)-β1 in the gut is well accepted [62,78], it is worth underlining that additional factors/cytokines, which are highly produced in the inflamed tissue of Crohn’s disease (CD) patients (e.g., tumor necrosis factor (TNF)–α), can stimulate stromal cells to synthesize elevated amounts of collagen, contributing to the pathogenesis of CD strictures [84,85]
Summary
The human gastrointestinal (GI) tract harbors the largest population of immune cells in the body and this is the result of a continuous exposure of the gut immune system to a complex and dynamic population of microorganisms (e.g., commensal bacterial, viral and fungal species) and dietary antigens [1]. Changes in the expression/function of such molecules contribute to initiate and/or propagate detrimental signals, which can eventually result in pathological conditions [2]. Among these molecules, a crucial enforcer is transforming growth factor (TGF)-β1, a cytokine produced by multiple lineages of leukocytes, stromal and epithelial cells and virtually targets all the gut mucosal cell types [3]. Binding of TGF-β1 to TβR2 leads to auto-phosphorylation of the receptor and subsequent recruitment of TβR1, to form a transmembrane heterodimer. At nuclear level, Smad can exert its inhibitory activity by interfering with the formation of functional receptor-activated Smad/Smad complexes as well as their binding to DNA [13]. We here review and discuss the role of TGF-β1/Smad axis in gut inflammation, fibrosis and cancer
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