School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, South Korea.
Transplantation Research Center, Catholic University of Korea, Seoul, South Korea.
Front Immunol. 2019 Apr 18;10:850. doi: 10.3389/fimmu.2019.00850. eCollection 2019.
TonEBP is a key transcriptional activator in macrophages with an M1 phenotype. High expression of TonEBP is associated with many inflammatory diseases. Heme oxygenase-1 (HO-1), a stress-inducible protein, is induced by various oxidative and inflammatory signals, and its expression is regarded as an adaptive cellular response to inflammation and oxidative injury. Here, we show that TonEBP suppresses expression of HO-1 by blocking Nrf2 binding to the HO-1 promoter, thereby inducing polarization of macrophages to the M1 phenotype. Inhibition of HO-1 expression or activity significantly reduced the inhibitory responses on M1 phenotype and stimulatory effects on M2 phenotype by TonEBP knockdown. Additional experiments showed that HO-1 plays a role in the paracrine anti-inflammatory effects of TonEBP knockdown in macrophages. Identification of HO-1 as a downstream effector of TonEBP provides new possibilities for improved therapeutic approaches to inflammatory diseases.
TonEBP 是 M1 表型巨噬细胞中的关键转录激活因子。TonEBP 的高表达与许多炎症性疾病有关。血红素加氧酶-1（HO-1）是一种应激诱导蛋白，可被各种氧化和炎症信号诱导，其表达被认为是细胞对炎症和氧化损伤的适应性反应。在这里，我们表明 TonEBP 通过阻止 Nrf2 结合到 HO-1 启动子上来抑制 HO-1 的表达，从而诱导巨噬细胞向 M1 表型极化。抑制 HO-1 的表达或活性可显著降低 TonEBP 敲低对 M1 表型的抑制反应和对 M2 表型的刺激作用。进一步的实验表明，HO-1 在 TonEBP 敲低的巨噬细胞旁分泌抗炎作用中发挥作用。鉴定 HO-1 作为 TonEBP 的下游效应因子为炎症性疾病的治疗方法提供了新的可能性。
