3-Hydroxykynurenine Regulates Lipopolysaccharide-Stimulated IL-6 Production and Protects against Endotoxic Shock in Mice

Masato Hoshi, Hisako Kubo, Tatsuya Ando, Chieko Tashita, Kentaro Nakamoto, Yasuko Yamamoto, Hiroyuki Tezuka, Kuniaki Saito

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Despite advances in our understanding of endotoxic shock, novel therapeutic interventions that can reduce the burden of sepsis remain elusive. Current treatment options are limited, and it is only through refinements in the ways that we deliver supportive care that mortality has fallen over the years. In this study, the role of kynurenine 3-monooxygenase (KMO) in immune regulation was examined in LPS-induced endotoxemia using KMO–/– and KMO+/+ mice treated with the KMO inhibitor Ro61-8048. We showed that LPS-induced or cecal ligation and puncture–induced mortality and hepatic IL-6 production increased in the absence of KMO, possibly involving increased activating transcription factor 4 (ATF4) signaling in hepatic macrophages. Moreover, treatment of septic mice with 3-hydroxykynurenine reduced mortality rates and inflammatory responses regardless of the presence or absence of KMO. According to our results, the administration of 3-hydroxykynurenine as part of the treatment approach for sepsis or as an adjuvant therapy might reduce the overproduction of IL-6, which is responsible for severe endotoxemia, and ultimately improve the survival rates of patients with sepsis.

Original languageEnglish
Pages (from-to)523-534
Number of pages12
JournalImmunoHorizons
Volume5
Issue number6
DOIs
Publication statusPublished - 01-06-2021

All Science Journal Classification (ASJC) codes

  • Immunology
  • Immunology and Allergy

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