Monteleone G, Boirivant M, Pallone F, MacDonald T T
Department of Internal Medicine, University Tor Vergata of Rome, Rome, Italy.
Mucosal Immunol. 2008 Nov;1 Suppl 1:S50-3. doi: 10.1038/mi.2008.55.
Inflammatory bowel diseases (IBDs) are caused by an aberrant and excessive local immune response to components of the bacterial microflora that are: poorly controlled by endogenous counter regulatory mechanisms such as the immunosuppressive cytokine transforming growth factor-beta1 (TGF-beta1). Studies in human IBD tissues have documented a disruption of TGF-beta1 signaling marked by a block in the phosphorylation of the activated TGF-beta receptor-associated signaling molecule, Smad3, caused by the upregulation of the intracellular inhibitor of Smad signaling, Smad7. Inhibition of Smad7 with a specific antisense oligonucleotide restores TGF-beta1/Smad3 signaling, resulting in a marked suppression of inflammatory cytokine production. The functional relevance of Smad7 in gut inflammation was confirmed by studies in murine models of IBD. In inflamed tissues of mice with colitis induced by either the trinitrobenzene sulfonic acid or oxazolone, p-Smad3 was low despite active TGF-beta1 being produced in excess. In vivo administration of Smad7 antisense oligonucleotides to mice with colitis restored TGF-beta1 signaling and decreased the synthesis of inflammatory molecules and the extent of gut damage. These data support a role for Smad7 in maintaining intestinal inflammation, and suggest that blocking Smad7 could be a promising way to dampen the ongoing inflammation in IBD.
炎症性肠病（IBD）是由对细菌微生物群成分的异常和过度局部免疫反应引起的，这种反应受到内源性反调节机制（如免疫抑制细胞因子转化生长因子-β1（TGF-β1））的控制不佳。对人类IBD组织的研究表明，TGF-β1信号传导存在破坏，其特征是由Smad信号传导的细胞内抑制剂Smad7上调导致活化的TGF-β受体相关信号分子Smad3的磷酸化受阻。用特异性反义寡核苷酸抑制Smad7可恢复TGF-β1/Smad3信号传导，从而显著抑制炎性细胞因子的产生。IBD小鼠模型的研究证实了Smad7在肠道炎症中的功能相关性。在由三硝基苯磺酸或恶唑酮诱导的结肠炎小鼠的炎症组织中，尽管过量产生了活性TGF-β1，但p-Smad3水平较低。对结肠炎小鼠体内给予Smad7反义寡核苷酸可恢复TGF-β1信号传导，并减少炎症分子的合成和肠道损伤程度。这些数据支持Smad7在维持肠道炎症中起作用，并表明阻断Smad7可能是减轻IBD中持续炎症的一种有前途的方法。
