Troncone Edoardo, Marafini Irene, Stolfi Carmine, Monteleone Giovanni
Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
Front Immunol. 2018 Jun 20;9:1407. doi: 10.3389/fimmu.2018.01407. eCollection 2018.
In physiological conditions, the activity of the intestinal immune system is tightly regulated to prevent tissue-damaging reactions directed against components of the luminal flora. Various factors contribute to maintain immune homeostasis and diminished production and/or function of such molecules trigger and/or propagate detrimental signals, which can eventually lead to chronic colitis and colon cancer. One such a molecule is transforming growth factor-β1 (TGF-β1), a cytokine produced by many inflammatory and non-inflammatory cells and targeting virtually all the intestinal mucosal cell types, with the down-stream effect of activating intracellular Smad2/3 proteins and suppressing immune reactions. In patients with inflammatory bowel diseases (IBD), there is defective TGF-β1/Smad signaling due to high Smad7, an inhibitor of TGF-β1 activity. Indeed, knockdown of Smad7 with a specific antisense oligonucleotide restores endogenous TGF-β1 activity, thereby inhibiting inflammatory pathways in patients with IBD and colitic mice. Consistently, mice over-expressing Smad7 in T cells develop severe intestinal inflammation in various experimental models. Smad7 expression is also upregulated in colon cancer cells, in which such a protein controls positively intracellular pathways that sustain neoplastic cell growth and survival. We here review the role of TGF-β1 and Smad7 in intestinal immunity, inflammation, and cancer.
在生理条件下，肠道免疫系统的活性受到严格调控，以防止针对管腔菌群成分的组织损伤反应。多种因素有助于维持免疫稳态，而此类分子产生和/或功能的减弱会触发和/或传播有害信号，最终可能导致慢性结肠炎和结肠癌。其中一种这样的分子是转化生长因子-β1（TGF-β1），它是一种由许多炎性和非炎性细胞产生的细胞因子，几乎作用于所有肠道黏膜细胞类型，具有激活细胞内Smad2/3蛋白并抑制免疫反应的下游效应。在炎症性肠病（IBD）患者中，由于TGF-β1活性抑制剂Smad7水平升高，导致TGF-β1/Smad信号传导缺陷。事实上，用特异性反义寡核苷酸敲低Smad7可恢复内源性TGF-β1活性，从而抑制IBD患者和结肠炎小鼠的炎症途径。同样，在各种实验模型中，T细胞中过表达Smad7的小鼠会发生严重的肠道炎症。Smad7在结肠癌细胞中的表达也上调，在这些细胞中，这种蛋白正向调控维持肿瘤细胞生长和存活的细胞内途径。我们在此综述TGF-β1和Smad7在肠道免疫、炎症和癌症中的作用。
