Murine FLIP transgene expressed on thyroid epithelial cells promotes resolution of granulomatous experimental autoimmune thyroiditis in DBA/1 mice
Murine FLIP transgene expressed on thyroid epithelial cells promotes resolution of granulomatous experimental autoimmune thyroiditis in DBA/1 mice
复制标题
DOI：
10.2353/ajpath.2007.060816
复制
发表时间：
2007-03-01
影响因子：
6
通讯作者：
Braley-Mullen, Helen
中科院分区：
文献类型：
--
作者：
Fang, Yujiang;Wei, Yongzhong;Braley-Mullen, Helen
肉芽肿性实验性自身免疫性甲状腺炎。（G-EAT）是由小鼠甲状腺球蛋白和白细胞介素-12体外激活的小鼠甲状腺球蛋白致敏的脾细胞诱导的。在WT供体脾细胞的野生型（WT）DBA/1受体中，甲状腺病变在第20天达到最严重程度，在第60天具有持续的炎症和广泛的纤维化。我们以前的研究表明，当病变消退或进展为纤维化时，FLIP和Fas配体[甲状腺上皮细胞（TEC）与炎症细胞]在小鼠中的表达部位不同。为了检验TEC表达FLIP将促进DBA/1小鼠中G-EAT早期消退的假设，产生在TEC上表达FLIP的转基因（Tg）DBA/1小鼠。在WT供体脾细胞的FLIP Tg（+）和Tg（-）同窝受者中，第20天G-EAT严重程度相当，但纤维化减少，Tg（+）受者中许多病变在第60天消退，而Tg-受者则不然。FLIP和Fas配体在第60天主要由Tg（+）受体中的TEC和Tg（-）受体中的炎性细胞表达。与Tg（-）受体相比，Tg（+）受体甲状腺炎性细胞凋亡增多，促炎细胞因子表达减少。这些结果与甲状腺上皮细胞上FLIP的转基因表达促进肉芽肿性实验性自身免疫性甲状腺炎的早期消退的假设一致。
Granulomatous experimental autoimmune thyroiditis. (G-EAT) is induced by mouse thyroglobulin-sensitized splenocytes activated in vitro with mouse thyroglobulin and interleukin-12. In wild-type (WT) DBA/1 recipients of WT donor splenocytes, thyroid lesions reach maximal severity at day 20, with ongoing inflammation and extensive fibrosis at day 60. Our previous studies indicated the site of expression of FLIP and Fas ligand [thyroid epithelial cells (TECs) versus inflammatory cells] differed in mice when lesions would resolve or progress to fibrosis. To test the hypothesis that expression of FLIP by TECs would promote earlier G-EAT resolution in DBA/1 mice, transgenic (Tg) DBA/1 mice expressing FLIP on TECs were generated. In FLIP Tg(+) and Tg(-) littermate recipients of WT donor splenocytes, G-EAT severity was comparable at day 20, but fibrosis was decreased, and many lesions resolved by day 60 in Tg(+) but not Tg- recipients. FLIP and Fas ligand were primarily expressed by TECs in Tg(+) recipients and by inflammatory cells in Tg(-) recipients at day 60. Apoptosis of inflammatory cells was greater, and expression of proinflammatory cytokines was decreased in thyroids of Tg(+) compared with Tg(-) recipients. These results are consistent with the hypothesis that transgenic expression of FLIP on thyroid epithelial cells promotes earlier resolution of granulomatous experimental autoimmune thyroiditis.