Transmembrane tumor necrosis factor is a potent inducer of colitis even in the absence of its secreted form
Transmembrane tumor necrosis factor is a potent inducer of colitis even in the absence of its secreted form
复制标题
DOI：
10.1053/j.gastro.2004.06.036
复制
发表时间：
2004-09-01
期刊：
影响因子：
29.4
通讯作者：
Mueller, C
中科院分区：
文献类型：
--
作者：
Corazza, N;Brunner, T;Mueller, C
背景和目标：肿瘤坏死因子（TNF）通过蛋白水解从26千道尔顿的跨膜前体蛋白裂解成分泌的17千道尔顿单体。Transmembrane（TM）和分泌的三聚体TNF具有生物活性，并且可以介导不同的活性。我们评估了完全抑制TNF加工对重组激活基因（RAG）2（-/-）小鼠转移CD 4 CD 45 RB（hi）T细胞的结肠炎过程的影响。研究方法：TNF-/-小鼠，转基因的不可切割的突变TNF基因，被用作CD 4 T细胞的供体，并在RAG 2（-/-）的背景下，也作为受体。疾病发展的动力学进行了比较，在TNF的情况下，在分泌的TNF的情况下，在分泌和tmTNF的存在下。观察期结束时的分析包括肠道组织病理学评估以及TNF和干扰素γ（IFN γ）表达细胞的定位。结果如下：在tmTNF转基因RAG 2（-/-）小鼠中完全阻止TNF分泌既不能阻止也不能延迟转基因小鼠TNF（tmTNF tg）CD 45 RB（hi）T细胞的不可切割跨膜突变体的疾病诱导。然而，转移的CD 4 T细胞的tmTNF表达不是疾病诱导所必需的，因为在TNF-/-CD 4 CD 45 RB（hi）T细胞的tmTNF RAG 2（-/-）受体中也观察到严重的结肠炎和体重减轻。在存在tmTNF的情况下，分泌的TNF的缺乏不影响TNF和干扰素-γ信使RNA（mRNA）表达细胞的频率和分布。结论：这些结果表明，TNF加工的特异性抑制剂不适合于调节TNF在肠道慢性炎症性疾病中的促炎和疾病诱导作用。
Background & Aims: Tumor necrosis factor (TNF) is cleaved proteolytically from a 26-kilodalton transmembrane precursor protein into secreted 17-kilodalton monomers. Transmembrane (tm) and secreted trimeric TNF are biologically active and may mediate distinct activities. We assessed the consequences of a complete inhibition of TNF processing on the course of colitis in recombination activating gene (RAG)2(-/-) mice on transfer of CD4 CD45RB(hi) T cells. Methods: TNF-/- mice, transgenic for a noncleavable mutant TNF gene, were used as donors of CD4 T cells, and, on a RAG2(-/-) background, also as recipients. Kinetics of disease development were compared in the absence of TNF, in the absence of secreted TNF, and in the presence of secreted and tmTNF. The analysis at the end of the observation period included the histopathologic assessment of the intestine and the localization of TNF and interferon gamma (IFNgamma)-expressing cells. Results: The complete prevention of TNF secretion in tmTNF transgenic RAG2(-/-) mice neither prevented nor delayed disease induction by transferred transgenic for a noncleavable transmembrane mutant of mouse TNF (tmTNF tg) CD4 CD45RB(hi) T cells. tmTNF expression by transferred CD4 T cells, however, was not required for disease induction because severe colitis and weight loss also were observed in tmTNF RAG2(-/-) recipients of TNF-/- CD4 CD45RB(hi) T cells. In the presence of tmTNF, the absence of secreted TNF did not affect frequency and distribution of TNF and interferon-gamma messenger RNA (mRNA)-expressing cells. Conclusions: These results indicate that specific inhibitors of TNF processing are not appropriate for modulating the pro-inflammatory and disease-inducing effects of TNF in chronic inflammatory disorders of the intestine.