Selective inhibition of interleukin-1 receptor-associated kinase 1 ameliorates lipopolysaccharide-induced sepsis in mice.

Abstract

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.

• Authors: Bin Pan, Jun Gao, Wei Chen, Cong Liu, Longmei Shang, Mengdi Xu, Chunling Fu, Shengyun Zhu, Mingshan Niu, Kailin Xu
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 85 Pg. 106597 (Aug 2020) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 32422509 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Benzamides
• Cytokines
• IRAK1 inhibitor Jh-X-119-01
• Lipopolysaccharides
• Pyrazoles
• Pyridines
• Interleukin-1 Receptor-Associated Kinases
• Irak1 protein, mouse

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Benzamides (pharmacology, therapeutic use)
• Cell Line
• Cytokines (immunology)
• Humans
• Interleukin-1 Receptor-Associated Kinases (antagonists & inhibitors, immunology)
• Lipopolysaccharides
• Lung (drug effects, immunology, pathology)
• Macrophages (drug effects, immunology)
• Male
• Mice, Inbred C57BL
• Pyrazoles (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)
• Sepsis (drug therapy, immunology, pathology)