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The Bisdioxopiperazine ICRF-193 Attenuates LPS-induced IL-1β Secretion by Macrophages
Ashleigh Brindle1, Callum Bainbridge1, Muganti R Kumar1
1Faculty of Health and Life Sciences, Northumbria University at Newcastle, Newcastle Upon Tyne, NE1 8ST, UK.
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 several IL1B gene sites, which may explain why ICRF-193 does not alter IL1B mRNA levels. 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. (165 words).
Insights
ICRF-193, a Topoisomerase II inhibitor, significantly reduced Interleukin-1β (IL-1β) secretion from human macrophages by approximately 40%. This finding suggests ICRF-193
Area of Science:
- Immunology
- Pharmacology
Background:
- Pathological secretion of Interleukin-1β (IL-1β) contributes to various diseases.
- Inhibiting IL-1β release from activated macrophages is a therapeutic target.
- Lipopolysaccharide (LPS) is a potent activator of macrophage IL-1β secretion.
Purpose of the Study:
- To investigate the effect of ICRF-193, a Topoisomerase II inhibitor, on IL-1β mRNA expression and secretion in human macrophages.
- To determine if ICRF-193 modulates IL-1β release in response to LPS stimulation.
Main Methods:
- Utilized an in vitro human macrophage model.
- Stimulated macrophages with Lipopolysaccharide (LPS).
- Assessed IL-1β secretion and IL1B mRNA expression following exposure to ICRF-193.
Main Results:
- Non-toxic doses of ICRF-193 reduced IL-1β secretion by approximately 40%.
- ICRF-193 did not affect IL1B mRNA transcription levels.
- No binding of Topoisomerase 2B (TOP2B) to IL1B gene sites was observed.
Conclusions:
- ICRF-193 effectively reduces IL-1β secretion from human macrophages.
- The mechanism of action does not involve altering IL1B gene transcription.
- ICRF-193 shows potential for treating inflammatory disorders due to its cost-effectiveness and the availability of prodrugs.
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