Doxorubicin and daunorubicin induce processing and release of interleukin-1β through activation of the NLRP3 inflammasome

Kristin A D Sauter, Lisa Wood, John Wong, Mihail Iordanov, Bruce E. Magun

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

Anthracyclines including doxorubicin and daunorubicin are commonly used for the treatment of both hematologic and solid tumors. Dose related adverse effects often limit the effectiveness of anthracyclines in chemotherapy. Drug-related systemic inflammation mediated by interleukin-1beta (IL-1β) has been implicated in contributing to these adverse effects. The molecular mechanisms underlying anthracycline-mediated expression and IL-1β release are not understood. Elucidating the molecular basis by which anthracyclines upregulate IL-1β activity may present opportunities to decrease the inflammatory consequences of these drugs. Here we demonstrate that doxorubicin induces a systemic increase in IL-1β and other inflammatory cytokines, chemokines and growth factors including TNFα, IL-6, Gro-α/CXCL1, CCL2/MCP-1, granulocyte colony stimulating factor (GCSF) and CXCL10/IP-10. Studies with IL-1R-deficient mice demonstrate that IL-1 signaling plays a role in doxorubicin-induced increases in IL-6 and GCSF. In vitro studies with doxorubicin and daunorubicin failed to induce expression of pro-IL-1β in unprimed murine bone marrow-derived macrophages (BMDM) but enhanced the expression of pro-IL-1β in BMDM that had previously been primed with LPS. Furthermore, doxorubicin and daunorubicin induced the processing and release of IL-1β from LPS-primed BMDM by providing danger signals that lead to assembly and activation of the inflammasome. The release of IL-1β required the expression of AS C, caspase-1 and NLRP3, demonstrating that doxorubicin and daunorubicin-induced inflammation is mediated by the NLRP3 inflammasome. As with other agents that induce activation of the NLRP3 inflammasome, the ability of doxorubicin to provide proinflammatory danger signals was inhibited by co-treatment of cells with ROS inhibitors or by incubating cells in high extracellular potassium. These studies suggest that proinflammatory responses to anthracycline chemotherapeutic agents are mediated, at least in part, by promoting the processing and release of IL-1β, and that some of the adverse inflammatory consequences that complicate chemotherapy with anthracyclines may be reduced by suppressing the actions of IL-1β.

Original languageEnglish (US)
Pages (from-to)1008-1016
Number of pages9
JournalCancer Biology and Therapy
Volume11
Issue number12
DOIs
StatePublished - Jun 15 2011

Fingerprint

Inflammasomes
Daunorubicin
Interleukin-1beta
Interleukin-1
Doxorubicin
Anthracyclines
Macrophages
Granulocyte Colony-Stimulating Factor
Interleukin-6
Inflammation
Drug Therapy
Caspase 1
Chemokines
Pharmaceutical Preparations
Intercellular Signaling Peptides and Proteins
Potassium
Up-Regulation

Keywords

  • Anthracycline
  • Cancer therapy
  • Daunorubicin
  • Doxorubicin
  • Inflammasome
  • Inflammation
  • Interleukin-1
  • Quality of life

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

Cite this

Doxorubicin and daunorubicin induce processing and release of interleukin-1β through activation of the NLRP3 inflammasome. / Sauter, Kristin A D; Wood, Lisa; Wong, John; Iordanov, Mihail; Magun, Bruce E.

In: Cancer Biology and Therapy, Vol. 11, No. 12, 15.06.2011, p. 1008-1016.

Research output: Contribution to journalArticle

Sauter, Kristin A D ; Wood, Lisa ; Wong, John ; Iordanov, Mihail ; Magun, Bruce E. / Doxorubicin and daunorubicin induce processing and release of interleukin-1β through activation of the NLRP3 inflammasome. In: Cancer Biology and Therapy. 2011 ; Vol. 11, No. 12. pp. 1008-1016.
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