Previously, we showed that an oligodeoxynucleotide with AAAG repeats (AAAG ODN) rescued mice from fatal acute lung injury (ALI) induced by influenza virus and inhibited production of tumor necrosis factor-α (TNF-α) in the injured lungs. However, the underlying mechanisms remain to be elucidated. Upon the bioinformatic analysis revealing that the AAAG ODN is consensus to interferon regulatory factor 5 (IRF5) binding site in the cis-regulatory elements of proinflammatory cytokines, we tried to explore whether the AAAG ODN could attenuate burn injury induced systemic inflammatory responses via inhibiting IRF5 pathway. Using the mouse model with sterile systemic inflammation induced by burn injury, we found that AAAG ODN prolonged the life span of the mice, decreased the expression of IRF5 at injured skin, reduced the production of TNF-α and IL-6 in blood and injured skin, and attenuated the ALI. Furthermore, AAAG ODN could bind IRF5 and inhibit the nuclear translocation of IRF5 in THP-1 cells. The data suggested that the AAAG ODN could act as a cytoplasmic decoy capable of interfering the function of IRF5, and be developed as a drug candidate for the treatment of inflammatory diseases.

译文

以前,我们显示了具有AAAG重复序列 (AAAG ODN) 的寡脱氧核苷酸将小鼠从流感病毒诱导的致命急性肺损伤 (ALI) 中拯救出来,并抑制了受伤肺中肿瘤坏死因子-α (TNF-α) 的产生。然而,潜在的机制仍有待阐明。通过生物信息学分析揭示AAAG ODN与促炎细胞因子顺式调节元件中干扰素调节因子5 (IRF5) 结合位点是共识,我们试图探索AAAG ODN是否可以通过抑制IRF5途径减轻烧伤引起的全身炎症反应。利用烧伤诱导的无菌全身炎症小鼠模型,我们发现AAAG ODN延长了小鼠的寿命,降低了损伤皮肤处IRF5的表达,减少了血液和损伤皮肤中TNF-α 和IL-6的产生,并减弱了ALI。此外,AAAG ODN可以结合IRF5并抑制IRF5在THP-1细胞中的核易位。数据表明,AAAG ODN可以充当能够干扰IRF5功能的细胞质诱饵,并被开发为治疗炎症性疾病的候选药物。

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