Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Dig Dis. 2012;30(4):392-5. doi: 10.1159/000338136. Epub 2012 Jul 12.
Immune function in the gut mucosa is tightly regulated to prevent deleterious tissue damaging responses to the indigenous microbiota. In animal models, negative regulatory molecules such as transforming growth factor β1 (TGFβ1) and interleukin (IL)-10 seem to be particularly important. Although IL-10 is made by macrophages, T cells and B cells, TGFβ1 is made by many non-lymphoid/myeloid cells, especially epithelial cells. We have been able to show that in the human gut, neutralization of TGFβ1 increases Th1 and Th17 responses. In IBD, however, especially Crohn's disease, exogenous TGFβ1 cannot inhibit inflammation because of a block in intracellular signalling mediated by Smad7. Knockdown of Smad7 allows endogenous TGFβ1 to dampen inflammation in mucosal tissues from Crohn's patients. We have also generated a mouse which over-expresses Smad7 in T cells. This animal develops more severe colitis in a number of different models, but the inflammation helps protect against colon cancer.
肠道黏膜中的免疫功能受到严格调控，以防止对固有微生物群产生有害的组织损伤反应。在动物模型中，转化生长因子β1（TGFβ1）和白细胞介素（IL）-10 等负调控分子似乎尤为重要。虽然 IL-10 由巨噬细胞、T 细胞和 B 细胞产生，但 TGFβ1 由许多非淋巴/髓样细胞产生，尤其是上皮细胞。我们已经能够证明，在人类肠道中，中和 TGFβ1 会增加 Th1 和 Th17 反应。然而，在炎症性肠病（IBD）中，尤其是克罗恩病，内源性 TGFβ1 由于 Smad7 介导的细胞内信号转导受阻而不能抑制炎症。Smad7 的敲低允许内源性 TGFβ1 抑制来自克罗恩病患者的黏膜组织的炎症。我们还生成了一种在 T 细胞中过表达 Smad7 的小鼠。该动物在多种不同模型中发展出更严重的结肠炎，但炎症有助于预防结肠癌。
