Induced disruption of the transforming growth factor beta type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable
Induced disruption of the transforming growth factor beta type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable
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DOI：
10.1182/blood.v100.2.560
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发表时间：
2002-07-15
期刊：
影响因子：
20.3
通讯作者：
Karlsson, S
中科院分区：
文献类型：
--
作者：
Levéen, P;Larsson, J;Karlsson, S
最近在转化生长因子β（TGF-β）信号传导缺陷的小鼠模型中的研究已经证明TGF-β是免疫功能的主要调节剂之一。TGF-β 1-null动物表现出影响多个器官的大量自身免疫性炎症，但试图通过骨髓移植将表型转移到正常动物仅导致轻微的炎性病变。我们想问的是，将TGF-β II型受体（TbetaRII）基因缺陷的骨髓移植给正常受体动物后，是否会产生致命的炎症表型。TbetaRII无效突变将产生细胞自主表型，其不能通过源自受体动物的内分泌或旁分泌TGF-β的影响而逆转。我们已经产生了条件性敲除小鼠，其中TbetaRII基因在用干扰素α或polyI：polyC诱导后被破坏。我们表明，在这些小鼠中通过polyl：polyC诱导TbetaRII基因破坏导致致命的炎症性疾病。重要的是，条件性基因敲除小鼠的骨髓转移到正常受体小鼠引起了类似的致命性炎症，无论是在移植前的供体动物中还是在移植后的受体动物中诱导TGF-β受体缺陷。这些结果表明，造血来源的细胞内的TGF-β信号传导缺陷足以引起小鼠中的致命炎症性疾病。该动物模型为进一步阐明TGF-β信号传导缺陷动物的致病机制以及TGF-β调节免疫功能的重要性提供了重要工具。
Recent studies in mouse models deficient in transforming growth factor beta (TGF-beta) signaling have documented TGF-beta as one of the major regulators of immune function. TGF-beta1-null animals demonstrated massive autoimmune inflammation affecting multiple organs, but attempts to transfer the phenotype to normal animals by bone marrow transplantation only resulted in minor inflammatory lesions. We wanted to ask whether a lethal inflammatory phenotype would develop following transplantation of bone marrow deficient for the TGF-beta type II receptor (TbetaRII) gene to normal recipient animals. The TbetaRII-null mutation would generate a cell autonomous phenotype that cannot be reverted by the influence of endocrine or paracrine TGF-beta derived from the recipient animal. We have generated conditional knockout mice In which the TbetaRII gene is disrupted upon Induction with interferon-alphabeta or polyl:polyC. We show that induction of TbetaRII gene disruption in these mice by polyl:polyC results in a lethal Inflammatory disease. Importantly, bone marrow from conditional knockout mice transferred to normal recipent mice caused a similar lethal inflammation, regardless of whether induction of TGF-beta receptor deficiency occurred In donor animals before, or In recipient animals after transplantation. These results show that TGF-beta signaling deficiency within cells of hematopoietic origin Is sufficient to cause a lethal Inflammatory disorder In mice. This animal model provides an Important tool to further clarity the pathogenic mechanisms in animals deficient for TGF-beta signaling and the Importance of TGF-beta to regulate immune functions.