title: Doxorubicin and daunorubicin induce processing and release of interleukin-1β through activation of the NLRP3 inflammasome.
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 TNF-α, IL-6, CXCL1/Gro-α, 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 proIL-1β in unprimed murine bone marrow-derived macrophages (BMDM) but enhanced the expression of proIL-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 ASC, 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.
authors.affiliation: Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, USA.
authors.forename: Kristin A D
authors.initials: KA
authors.lastname: Sauter
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Wood
authors.forename: John
authors.initials: J
authors.lastname: Wong
authors.forename: Mihail
authors.initials: M
authors.lastname: Iordanov
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Magun
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003630:Daunorubicin / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011188:Potassium / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D020170:Caspase 1; D011188:Potassium; D003630:Daunorubicin