Ocular Surface Center, Cullen Eye Institute, and the Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA.
Am J Pathol. 2011 Oct;179(4):1807-14. doi: 10.1016/j.ajpath.2011.06.030. Epub 2011 Aug 16.
We investigated the role of CD4(+) T-cell-produced interferon (IFN)-γ on corneal epithelial apoptosis in a murine desiccating stress (DS) model that resembles Sjögren's syndrome. The DS model was generated in C57BL/6 (B6) and B6 IFN-γ-knockout (B6γKO) mice. Adoptive transfer of CD4(+) T cells from DS-exposed donor to recombination activating gene (RAG)-1(-/-) recipient mice and topical neutralization of IFN-γ were performed to determine whether IFN-γ produced by pathogenic CD4(+) T cells promotes corneal epithelial apoptosis. Apoptosis in corneal epithelia was assessed by evaluating the expression and activity of caspases 3, 8, and 9. The activation of caspase-8 mediated increased corneal epithelial apoptosis in B6 mice after DS, and this was exacerbated by subconjunctival IFN-γ injection. B6γKO mice were resistant to DS-induced apoptosis; however, B6γKO mice receiving IFN-γ developed apoptosis similar to that observed in B6 wild-type mice. Adoptive transfer of CD4(+) T cells from donors subjected to DS increased corneal epithelial apoptosis via activation of caspase-8 in recipients, similar to that in the donor mice. Topical neutralization of IFN-γ in adoptive transfer recipients decreased corneal epithelial apoptosis. DS, IFN-γ administration, or CD4(+) T-cell adoptive transfer had no effect on the expression and activation of the intrinsic apoptosis mediator, caspase-9. CD4(+) T-cell-produced IFN-γ plays a pivotal role in DS-induced corneal epithelial apoptosis via activation of the extrinsic apoptotic pathway.
我们研究了 CD4(+) T 细胞产生的干扰素（IFN）-γ 在类似于干燥综合征的干燥应激（DS）模型中对角膜上皮细胞凋亡的作用。DS 模型是在 C57BL/6（B6）和 B6 IFN-γ 敲除（B6γKO）小鼠中生成的。从 DS 暴露供体向重组激活基因（RAG）-1(-/-)受体小鼠过继转移 CD4(+) T 细胞和局部中和 IFN-γ，以确定由致病性 CD4(+) T 细胞产生的 IFN-γ是否促进角膜上皮细胞凋亡。通过评估半胱氨酸天冬氨酸蛋白酶 3、8 和 9 的表达和活性来评估角膜上皮细胞的凋亡。DS 后，B6 小鼠中 caspase-8 的激活介导了角膜上皮细胞凋亡的增加，而结膜下注射 IFN-γ 则加剧了这种增加。B6γKO 小鼠对 DS 诱导的凋亡有抵抗力；然而，接受 IFN-γ 的 B6γKO 小鼠发展出类似于 B6 野生型小鼠的凋亡。从 DS 供体过继转移的 CD4(+) T 细胞增加了受体中的 caspase-8 激活，从而增加了角膜上皮细胞凋亡，类似于供体小鼠。在过继转移受体中局部中和 IFN-γ 可减少角膜上皮细胞凋亡。DS、IFN-γ 给药或 CD4(+) T 细胞过继转移对内在凋亡介质 caspase-9 的表达和激活没有影响。CD4(+) T 细胞产生的 IFN-γ 通过激活外在凋亡途径在 DS 诱导的角膜上皮细胞凋亡中起关键作用。
