title: Production of IL-1β by bone marrow-derived macrophages in response to chemotherapeutic drugs: synergistic effects of doxorubicin and vincristine.
abstract: Cytotoxic chemotherapeutic drugs, especially when used in combination, are widely employed to treat a variety of cancers in patients but often lead to serious symptoms that negatively affect physical functioning and quality of life. There is compelling evidence that implicates cytotoxic chemotherapy-induced inflammation in the etiology of these symptoms. Because IL-1β plays a central role as an initiator cytokine in immune responses, we compared doxorubicin, a drug known to induce IL-1β production, with ten other commonly prescribed chemotherapeutic drugs in their ability to lead to processing and secretion of IL-1β by primary mouse macrophages. Seven of them (melphalan, cisplatin, vincristine, etoposide, paclitaxel, methotrexate, and cytarabine) caused the production of IL-1β in cells pretreated with lipopolysaccharide. When delivered in combination with doxorubicin, one of the drugs, vincristine, was also capable of synergistically activating the NLRP3-dependent inflammasome and increasing expression of IL-1β, IL-6, and CXCL1. The absence of TNF-α and IL-1 signaling caused a partial reduction in the production of mature IL-1β. Three small-molecule inhibitors known to suppress activity of kinases situated upstream of mitogen-activated kinases (MAPKs) inhibited the expression of IL-1β, IL-6, and CXCL1 when doxorubicin and vincristine were used singly or together, so specific kinase inhibitors may be useful in reducing inflammation in patients receiving chemotherapy.
authors.affiliation: School of Nursing; Massachusetts General Hospital Institute of Health Professions; Boston, MA USA.
authors.forename: John
authors.initials: J
authors.lastname: Wong
authors.affiliation: School of Nursing; Massachusetts General Hospital Institute of Health Professions; Boston, MA USA.
authors.forename: Lisa T
authors.initials: LT
authors.lastname: Tran
authors.affiliation: Department of Dermatology; Oregon Health & Science University; Portland, OR USA.
authors.forename: Eli A
authors.initials: EA
authors.lastname: Magun
authors.affiliation: School of Nursing; Massachusetts General Hospital Institute of Health Professions; Boston, MA USA.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Magun
authors.affiliation: School of Nursing; Massachusetts General Hospital Institute of Health Professions; Boston, MA USA.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Wood
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D058847:Inflammasomes / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction; D014750:Vincristine / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C475829:CXCL1 protein, human; D002352:Carrier Proteins; D054360:Chemokine CXCL1; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D012333:RNA, Messenger; D014750:Vincristine; D004317:Doxorubicin
keywords: cytokines; inflammasome; nilotinib; ponatinib; sorafenib