Gene Therapy Program, Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, 533 Bolivar St., New Orleans, LA 70112, USA.
FASEB J. 2011 Jul;25(7):2387-98. doi: 10.1096/fj.10-175299. Epub 2011 Apr 6.
Emerging evidence suggests that the tumor suppressor p53 is also a crucial regulator for many physiological processes. Previous observations indicate that p53 suppresses inflammation by inhibiting inflammatory antigen-presenting cells. To investigate the potential role of p53 in autoimmune effector T cells, we generated p53(null)CD45.1 mice by crossing p53(null)CD45.2 and CD45.1 mice. We demonstrate that p53(null)CD45.1 mice spontaneously developed autoimmunity, with a significant increase in IL-17-producing Th17 effectors in their lymph nodes (4.7 ± 1.0%) compared to the age-matched counterparts (1.9 ± 0.8% for p53(null)CD45.2, 1.1 ± 0.2% for CD45.1, and 0.5 ± 0.1% for CD45.2 mice). Likewise, p53(null)CD45.1 mice possess highly elevated serum levels of inflammatory cytokines IL-17 and IL-6. This enhanced Th17 response results largely from an increased sensitivity of p53(null)CD45.1 T cells to IL-6-induced STAT3 phosphorylation. Administration of STAT3 inhibitor S31-201 (IC50 of 38.0 ± 7.2 μM for IL-6-induced STAT3 phosphorylation), but not PBS control, to p53(null)CD45.1 mice suppressed Th17 effectors and alleviated autoimmune pathology. This is the first report revealing that p53 activity in T cells suppresses autoimmunity by controlling Th17 effectors. This study suggests that p53 serves as a guardian of immunological functions and that the p53-STAT3-Th17 axis might be a therapeutic target for autoimmunity.
新出现的证据表明，肿瘤抑制因子 p53 也是许多生理过程的关键调节因子。先前的观察表明，p53 通过抑制炎症性抗原呈递细胞来抑制炎症。为了研究 p53 在自身免疫效应 T 细胞中的潜在作用，我们通过将 p53(null)CD45.2 和 CD45.1 小鼠杂交，生成了 p53(null)CD45.1 小鼠。我们证明，p53(null)CD45.1 小鼠自发地发生了自身免疫，其淋巴结中产生 IL-17 的 Th17 效应物显著增加（4.7 ± 1.0%），与年龄匹配的对照相比（p53(null)CD45.2 为 1.9 ± 0.8%，CD45.1 为 1.1 ± 0.2%，CD45.2 为 0.5 ± 0.1%）。同样，p53(null)CD45.1 小鼠具有高度升高的炎症细胞因子 IL-17 和 IL-6 的血清水平。这种增强的 Th17 反应主要是由于 p53(null)CD45.1 T 细胞对 IL-6 诱导的 STAT3 磷酸化的敏感性增加所致。向 p53(null)CD45.1 小鼠施用 STAT3 抑制剂 S31-201（IL-6 诱导的 STAT3 磷酸化的 IC50 为 38.0 ± 7.2 μM），而不是 PBS 对照，可抑制 Th17 效应物并减轻自身免疫病理学。这是第一项揭示 T 细胞中 p53 活性通过控制 Th17 效应物来抑制自身免疫的报告。这项研究表明，p53 是免疫功能的守护者，p53-STAT3-Th17 轴可能是自身免疫的治疗靶点。
