Inflammatory signals in inflammatory bowel diseases = Segnali infiammatori nelle malattie infiammatorie intestinali

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract with a multifactorial pathophysiology. Accumulating evidence suggests that both Crohn’s disease (CD) and ulcerative colitis (UC), the two major IBD, arise because of the action of multiple environmental and genetic factors, which ultimately promote an excessive immune response against component of the luminal flora [1, 2]. Defects in counter-regulatory mechanisms are also documentable in inflamed tissue of IBD patients and supposed to amplify the pathological process. For instance, in both IBD there is diminished activity of transforming growth factor (TGF)-β1, an immunosuppressive cytokine that delivers negative signals in many immune cells [3]. Such a defect has been associated with elevated levels of Smad7, an intracellular protein that binds to TGF-β receptor type I and inhibits TGF-β1-induced signaling [4, 5]. Consistently, inhibition of Smad7 with a specific antisense oligonucleotide (AS) restores TGF-β1 signaling and reduces inflammatory pathways in both in vitro and in vivo models of intestinal inflammation [5, 6]. The mechanisms/factors regulating Smad7 expression in IBD mucosa are not fully understood. Our previous studies showed that Smad7 is not regulated at transcriptional level as no significant change in Smad7 RNA expression was found between IBD and normal control samples [7]. It was also shown that, in IBD, high Smad7 is sustained by post-transcriptional mechanisms that enhance its stability [7]. Indeed, Smad7 is highly acetylated on lysine residues and this protein modification prevents ubiquitination-driven proteasomal-mediated degradation of Smad7 [8]. Analysis of factors involved in the control of Smad7 acetylation revealed that IBD-associated inflammation is marked by elevated levels of p300, a protein with intrinsic acetyltransferase activity [7]. Silencing of p300 with specific siRNA partially reduced Smad7 content [7], suggesting the existence of further mechanisms/factors involved in the control of Smad7 protein stability. One such a factor could be Sirt1, a class III histone deacetylase, which enhances ubiquitination-driven proteasome-mediated degradation of various inflammatory proteins [9]. Notably, Sirt1 expression is reduced in IBD tissue and activation of Sirt1 attenuates inflammatory signals in the gut, raising the possibility that such a defect could contribute to perpetuate pathogenic responses in the gut [10]. In an attempt to dissect the mechanisms that suppress Sirt1 in IBD, we showed that stimulation of control intestinal mucosal cells with tumor necrosis factor (TNF)-α and interleukin (IL)-21 reduced Sirt1 expression while blockade of the activity of these 2 cytokines up-regulated Sirt1 in IBD LPMC [10]. This suggests that reduction of Sirt1 in IBD can rely on factors generated within the inflammatory microenvironment. Based upon these findings, we hypothesized that, in IBD mucosa, reduced Sirt1 activity contributes to enhance Smad7 protein stability and expression, while high Smad7 helps propagate signals that culminate in Sirt1 down-regulation. Therefore, the aim of the present study was to investigate whether, in IBD, there is a reciprocal regulatory mechanism between Smad7 and Sirt1.