Topoisomerase II Inhibition Attenuates LPS-induced IL- 1β Secretion by Macrophages

Abstract

Abstract Inhibiting pathological secretion of Interleukin-1β 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-1β secretion. These macrophage-like cells readily secrete IL-1β in response to Lipopolysaccharide (LPS). Upon exposure to a non-toxic dose of ICRF-193, IL-1β secretion was diminished by ~ 40%; however, level of transcription of IL1B was unaffected. We show that there was no Topoisomerase 2B (TOP2B) binding to IL1B gene proximal sites, confirming that it is not involved directly in mediating the transcription of IL1B and hence why ICRF-193 does not alter IL1B mRNA levels. Quantification of Topoisomerase isoforms suggests that TOP2B plays a role in mediating the effects of ICRF-193 on IL-1β secretion. Hence, we show for the first time that ICRF-193 can reduce IL-1β 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. (196 words)