The Bisdioxopiperazine ICRF-193 Attenuates LPS-induced IL-1 beta Secretion by Macrophages

Inhibiting pathological secretion of Interleukin-1 beta has shown beneficial effects in disease models and in the clinic and thus there is interest in finding inhibitors that can reduce its release from macrophages in response to their activation by foreign pathogens. We used an in vitro human macrophage model to investigate whether ICRF-193, a Topoisomerase II inhibitor could modulate IL1B mRNA expression and IL-1 beta secretion. These macrophage-like cells readily secrete IL-1 beta in response to Lipopolysaccharide ( LPS). Upon exposure to a non-toxic dose of ICRF-193, IL-1 beta secretion was diminished by similar to 40%; however, level of transcription of IL1B was unaffected. We show that there was no Topoisomerase 2B (TOP2B) binding to several IL1B gene sites, which may explain why ICRF193 does not alter IL1B mRNA levels. Hence, we show for the first time that ICRF-193 can reduce IL-1 beta secretion. Its low cost and the development of water-soluble prodrugs of ICRF-193 warrants its further investigation in the modulation of pathological secretion of this cytokine for the treatment of inflammatory disorders. (165 words).

Automated summary

ICRF-193, a Topoisomerase II inhibitor, can reduce the secretion of IL-1 beta by inhibiting its release from macrophages. The transcription level of IL1B is unaffected by ICRF-193. Therefore, ICRF-193 shows potential as a treatment for inflammatory disorders by modulating IL-1 beta secretion.