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

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-1 beta) has been implicated in contributing to these adverse effects. The molecular mechanisms underlying anthracycline-mediated expression and IL-1 beta release are not understood. Elucidating the molecular basis by which anthracyclines upregulate IL-1 beta activity may present opportunities to decrease the inflammatory consequences of these drugs. Here we demonstrate that doxorubicin induces a systemic increase in IL-1 beta and other inflammatory cytokines, chemokines and growth factors including TNF alpha, IL-6, Gro-alpha/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-1 beta in unprimed murine bone marrow-derived macrophages (BMDM) but enhanced the expression of pro-IL-1 beta in BMDM that had previously been primed with LPS. Furthermore, doxorubicin and daunorubicin induced the processing and release of IL-1 beta from LPS-primed BMDM by providing danger signals that lead to assembly and activation of the inflammasome. The release of IL-1 beta 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-1 beta and that some of the adverse inflammatory consequences that complicate chemotherapy with anthracyclines may be reduced by suppressing the actions of IL-1 beta