Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases.
Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases.
复制标题
DOI：
10.1084/jem.20070906
复制
发表时间：
2008-02-18
期刊：
影响因子：
--
通讯作者：
Kollias G
中科院分区：
文献类型：
--
作者：
Armaka M;Apostolaki M;Jacques P;Kontoyiannis DL;Elewaut D;Kollias G
肿瘤坏死因子（TNF）是各种关节炎性疾病和炎症性肠病（IBD）发病机制的关键。抗TNF疗法已被证明在这些疾病的临床治疗中是成功的，但仍然缺乏对TNF功能的机制理解。我们已经研究了TNF功能在这些疾病中的早期细胞机制，使用一个已建立的TNF转基因模型，该模型发展为脊柱关节炎样疾病，其特征在于外周关节炎、骶髂关节炎、附着点炎和克罗恩病样IBD。骨髓移植实验表明，关节炎的发展需要TNF受体I（TNFRI）在抗辐射隔室中表达，这也是已知的在相同模型中克罗恩病样IBD的发展中TNF的充分靶点。滑膜成纤维细胞和肠肌成纤维细胞的早期激活也可以通过基质金属蛋白酶及其抑制剂的表达紊乱来证明。值得注意的是，间充质细胞中选择性Cre/loxP介导的TNFRI表达导致完全关节炎-脊柱关节炎和肠表型，表明间充质细胞是这些病理中TNF的主要和足够的靶标。我们的研究结果为TNF在肠道和关节病理中的功能提供了一种新的机制视角，并表明早期常见的细胞通路也可以解释人类疾病中经常观察到的滑膜-肠道轴。
Tumor necrosis factor (TNF) is key to the pathogenesis of various arthritic diseases and inflammatory bowel disease (IBD). Anti-TNF therapies have proved successful in the clinical treatment of these diseases, but a mechanistic understanding of TNF function is still lacking. We have investigated early cellular mechanisms of TNF function in these diseases using an established TNF transgenic model, which develops a spondyloarthritis-like disease characterized by peripheral joint arthritis, sacroiliitis, enthesitis, and Crohn's-like IBD. Bone marrow grafting experiments demonstrated that development of arthritis requires TNF receptor I (TNFRI) expression in the radiation-resistant compartment, which is also known to be a sufficient target of TNF in the development of Crohn's-like IBD in the same model. Early activation of synovial fibroblasts and intestinal myofibroblasts could also be demonstrated by perturbed expression of matrix metalloproteases and their inhibitors. Notably, selective Cre/loxP-mediated TNFRI expression in mesenchymal cells resulted in a fully arthritic–spondyloarthritic and intestinal phenotype, indicating that mesenchymal cells are primary and sufficient targets of TNF in these pathologies. Our results offer a novel mechanistic perspective for TNF function in gut and joint pathologies and indicate early common cellular pathways that may also explain the often observed synovial–gut axis in human disease.
登录
查看更多内容
影响因子：
32.4
作者：
Kontoyiannis, D;Pasparakis, M;Kollias, G
通讯作者：
Kollias, G
不同的区域控制转基因小鼠不同组织中α1（VI）胶原蛋白启动子的转录激活。
DOI：
10.1083/jcb.135.4.1163
发表时间：
1996-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Braghetta P;Fabbro C;Piccolo S;Marvulli D;Bonaldo P;Volpin D;Bressan GM
通讯作者：
Bressan GM
DOI：
10.1084/jem.20020281
发表时间：
2002-12-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kontoyiannis D;Boulougouris G;Manoloukos M;Armaka M;Apostolaki M;Pizarro T;Kotlyarov A;Forster I;Flavell R;Gaestel M;Tsichlis P;Cominelli F;Kollias G
通讯作者：
Kollias G
影响因子：
27.4
作者：
Tchetverikov, I;Lard, LR;Hanemaaijer, R
通讯作者：
Hanemaaijer, R
影响因子：
11.4
作者：
KEFFER, J;PROBERT, L;KOLLIAS, G
通讯作者：
KOLLIAS, G