Interleukin-1 receptor-associated kinases (IRAKs), particularly IRAK1 and IRAK4, are important in transducing signal from Toll-like receptor 4. We interrogated if a selective inhibition of IRAK1 could alleviate lipopolysaccharide (LPS)-induced sepsis. In this study, we tested the impact of a novel selective IRAK1 inhibitor Jh-X-119-01 on LPS-induced sepsis in mice. Survival at day 5 was 13.3% in control group where septic mice were treated by vehicle, while the values were 37.5% (p = 0.046, vs. control) and 56.3% (p = 0.003, vs. control) for 5 mg/kg and 10 mg/kg Jh-X-119-01-treated mice. Jh-X-119-01 alleviated lung injury and reduced production of TNFα and IFNγ in peritoneal macrophages. Jh-X-119-01 decreased phosphorylation of NF-κB and mRNA levels of IL-6 and TNFα in LPS-treated macrophages in vitro. Jh-X-119-01 selectively inhibited IRAK1 phosphorylation comparing with a non-selective IRAK1/4 inhibitor which simultaneously inhibited phosphorylation of IRAK1 and IRAK4. Both Jh-X-119-01 and IRAK1/4 inhibitor increased survival of septic mice, but Jh-X-119-01-treated mice had higher blood CD11b⁺ cell counts than IRAK1/4 inhibitor-treated ones [24 h: (1.18 ± 0.26) × 10⁶/ml vs. (0.79 ± 0.20) × 10⁶/ml, p = 0.001; 48 h: (1.00 ± 0.30) × 10⁶/ml vs. (0.67 ± 0.23) × 10⁶/ml, p = 0.042]. IRAK1/4 inhibitor induced more apoptosis of macrophages than Jh-X-119-01 did in vitro. IRAK1/4 inhibitor decreased protein levels of anti-apoptotic BCL-2 and MCL-1 in RAW 264.7 and THP-1 cells, an effect not seen in Jh-X-119-01-treated cells. In conclusion, Jh-X-119-01 selectively inhibited activation of IRAK1 and protected mice from LPS-induced sepsis. Jh-X-119-01 showed less toxicity on macrophages comparing with a non-selective IRAK1/4 inhibitor.

白介素1受体相关的激酶（IRAK），尤其是IRAK1和IRAK4，在转导Toll样受体4的信号中很重要。我们询问IRAK1的选择性抑制是否可以减轻脂多糖（LPS）引起的败血症。在这项研究中，我们测试了新型选择性IRAK1抑制剂Jh-X-119-01对LPS诱导的小鼠败血症的影响。在对照组中，通过媒剂处理败血病小鼠的第5天存活率为13.3％，而分别为37.5％（与对照组相比 ，p = 0.046 ）和56.3％（与对照组相比，p  = 0.003）。对照）5 mg / kg和10 mg / kg Jh-X-119-01处理的小鼠。Jh-X-119-01减轻了肺损伤，并减少了腹膜巨噬细胞中TNFα和IFNγ的产生。Jh-X-119-01降低了LPS处理的巨噬细胞中NF-κB的磷酸化以及IL-6和TNFα的mRNA水平。与非选择性IRAK1 / 4抑制剂（同时抑制IRAK1和IRAK4的磷酸化）相比，Jh-X-119-01选择性抑制IRAK1的磷酸化。Jh-X-119-01和IRAK1 / 4抑制剂均可增加败血症小鼠的存活率，但Jh-X-119-01处理的小鼠的血液CD11b ⁺细胞计数高于IRAK1 / 4抑制剂治疗的小鼠[24 h：（ 1.18±0.26）×10 ⁶ / ml与（0.79±0.20）×10 ⁶ / ml，p = 0.001；48小时：（1.00±0.30）×10 ⁶ / ml的对（0.67±0.23）×10 ⁶ / ml时，p  = 0.042]。IRAK1 / 4抑制剂比Jh-X-119-01体外诱导的巨噬细胞凋亡更多。IRAK1 / 4抑制剂可降低RAW 264.7和THP-1细胞中抗凋亡BCL-2和MCL-1的蛋白水平，这种作用在Jh-X-119-01处理的细胞中未见。总之，Jh-X-119-01选择性抑制IRAK1的活化并保护小鼠免受LPS诱导的败血症的侵害。与非选择性IRAK1 / 4抑制剂相比，Jh-X-119-01对巨噬细胞的毒性较小。