Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.
J Virol. 2012 Oct;86(19):10377-83. doi: 10.1128/JVI.01340-12. Epub 2012 Jul 11.
Neurodegenerative diseases are typically associated with an activation of glia and an increased level of cytokines. In our previous studies of prion disease, the cytokine response in the brains of clinically sick scrapie-infected mice was restricted to a small group of cytokines, of which IL-12p40, CCL2, and CXCL10 were present at the highest levels. The goal of our current research was to determine the relationship between cytokine responses, gliosis, and neuropathology during prion disease. Here, in time course studies of C57BL/10 mice intracerebrally inoculated with 22L scrapie, abnormal protease-resistant prion protein (PrPres), astrogliosis, and microgliosis were first detected at 40 days after intracerebral scrapie inoculation. In cytokine studies, IL-12p40 was first elevated by 60 days; CCL3, IL-1β, and CXCL1 were elevated by 80 days; and CCL2 and CCL5 were elevated by 115 days. IL-12p40 showed the most extensive increase throughout disease and was 30-fold above control levels at the terminal stage. Because of the early onset and dramatic elevation of IL-12p40 during scrapie, we investigated whether IL-12p40 contributed to the development of prion disease neuropathogenesis by using three different scrapie strains (22L, RML, 79A) to infect knockout mice in which the gene encoding IL-12p40 was deleted. We also studied knockout mice lacking IL-12p35, which combines with IL-12p40 to form active IL-12 heterodimers. In all instances, knockout mice did not differ from control mice in survival time, clinical tempo, or levels of spongiosis, gliosis, or PrPres in the brain. Thus, neither IL-12p40 nor IL-12p35 molecules were required for prion disease-associated neurodegeneration or neuroinflammation.
神经退行性疾病通常与神经胶质细胞的激活和细胞因子水平的升高有关。在我们之前对朊病毒病的研究中，临床患病的瘙痒感染小鼠大脑中的细胞因子反应仅限于一小部分细胞因子，其中 IL-12p40、CCL2 和 CXCL10 的水平最高。我们目前研究的目标是确定朊病毒病期间细胞因子反应、神经胶质增生和神经病理学之间的关系。在这里，在用 22L 瘙痒接种脑内的 C57BL/10 小鼠的时间过程研究中，异常蛋白酶抗性朊病毒蛋白（PrPres）、星形胶质细胞增生和小胶质细胞增生首先在脑内瘙痒接种后 40 天检测到。在细胞因子研究中，IL-12p40 最早在 60 天升高；CCL3、IL-1β 和 CXCL1 在 80 天升高；CCL2 和 CCL5 在 115 天升高。IL-12p40 在整个疾病过程中显示出最广泛的增加，在终末期比对照水平高 30 倍。由于瘙痒期间 IL-12p40 的早期发生和显著升高，我们通过用三种不同的瘙痒株（22L、RML、79A）感染缺失编码 IL-12p40 的基因的基因敲除小鼠来研究 IL-12p40 是否有助于朊病毒病神经发病机制的发展。我们还研究了缺乏 IL-12p35 的基因敲除小鼠，IL-12p35 与 IL-12p40 结合形成活性 IL-12 异二聚体。在所有情况下，基因敲除小鼠在存活时间、临床病程或大脑中的海绵状变性、神经胶质增生或 PrPres 水平方面与对照小鼠没有差异。因此，IL-12p40 或 IL-12p35 分子都不是与朊病毒病相关的神经退行性变或神经炎症所必需的。
