Duquesne University, Department of Biological Sciences, Pittsburgh, PA 15282, United States.
Gladstone Institute of Virology and Immunology, San Francisco, CA 94158, United States.
Cytokine. 2018 Nov;111:373-381. doi: 10.1016/j.cyto.2018.10.001. Epub 2018 Oct 6.
Interleukin 1β is a pro-inflammatory cytokine important for both normal immune responses and chronic inflammatory diseases. The regulation of the 31 kDa proIL-1β precursor coded by the IL1B gene has been extensively studied in myeloid cells, but not in lymphoid-derived CD4 T cells. Surprisingly, we found that some CD4 T cell subsets express higher levels of proIL-1β than unstimulated monocytes, despite relatively low IL1B mRNA levels. We observed a significant increase in IL1B transcription and translation in CD4 T cells upon ex vivo CD3/CD28 activation, and a similar elevation in the CCR5+ effector memory population compared to CCR5- T cells in vivo. The rapid and vigorous increase in IL1B gene transcription for stimulated monocytes has previously been associated with the presence of Spi-1/PU.1 (Spi1), a myeloid-lineage transcription factor, pre-bound to the promoter. In the case of CD4 T cells, this increase occurred despite the lack of detectable Spi1 at the IL1B promoter. Additionally, we found altered epigenetic regulation of the IL1B locus in CD3/CD28-activated CD4 T cells. Unlike monocytes, activated CD4 T cells possess bivalent H3K4me3+/H3K27me3+ nucleosome marks at the IL1B promoter, reflecting low transcriptional activity. These results support a model in which the IL1B gene in CD4 T cells is transcribed from a low-activity bivalent promoter independent of Spi1. Accumulated cytoplasmic proIL-1β may ultimately be cleaved to mature 17 kDa bioactive IL-1β, regulating T cell polarization and pathogenic chronic inflammation.
白细胞介素 1β（IL-1β）是一种促炎细胞因子，对于正常免疫反应和慢性炎症性疾病都非常重要。IL1B 基因编码的 31kDa 前体 proIL-1β 的调节在髓系细胞中得到了广泛研究，但在淋巴样来源的 CD4 T 细胞中尚未研究。令人惊讶的是，我们发现一些 CD4 T 细胞亚群表达的 proIL-1β 水平高于未刺激的单核细胞，尽管其 IL1B mRNA 水平相对较低。我们观察到 CD4 T 细胞在体外 CD3/CD28 激活后 IL1B 转录和翻译显著增加，并且在体内 CCR5+效应记忆群体中与 CCR5-T 细胞相比，IL1B 转录的增加相似。先前已发现刺激的单核细胞中 IL1B 基因转录的快速和剧烈增加与 Spi-1/PU.1（Spi1）的存在有关，Spi1 是一种髓系谱系转录因子，预先结合在启动子上。对于 CD4 T 细胞，尽管在 IL1B 启动子处未检测到可检测的 Spi1，但这种增加仍然发生。此外，我们发现 CD3/CD28 激活的 CD4 T 细胞中 IL1B 基因座的表观遗传调控发生改变。与单核细胞不同，激活的 CD4 T 细胞在 IL1B 启动子上具有双价 H3K4me3+/H3K27me3+核小体标记，反映出低转录活性。这些结果支持一种模型，即 CD4 T 细胞中的 IL1B 基因从 Spi1 独立的低活性双价启动子转录。积累的细胞质 proIL-1β 最终可能被切割为成熟的 17kDa 生物活性 IL-1β，调节 T 细胞极化和致病性慢性炎症。
