CYTOTOXIC CANCER CHEMOTHERAPEUTIC AGENTS INDUCE IL-1β PRODUCTION BY IMMUNE CELLS

2.50
Hdl Handle:
http://hdl.handle.net/10755/211560
Type:
Research Study
Title:
CYTOTOXIC CANCER CHEMOTHERAPEUTIC AGENTS INDUCE IL-1β PRODUCTION BY IMMUNE CELLS
Abstract:
Purpose: Cancer patients treated with mechanistically distinct cytotoxic chemotherapeutic agents often experience a cluster of symptoms including, fatigue, lethargy, decreased appetite, sleep disturbance, difficulty thinking, and pain. These symptoms have a profound negative effect on physical functioning and quality of life (QOL). Our research group proposes that CTRS: (i) are mechanistically understandable at molecular and cellular levels and (ii) the onset and severity of CTRS are amenable for therapeutic modulation. It has long been recognized that these symptoms are remarkably similar to those associated with sickness behavior, a normal physiological response to activation of the innate immune system, in which pro-inflammatory cytokines such as IL-1β play a central role. The purpose of the present study is to determine whether cytotoxic chemotherapeutic agents from a variety of drug classes share a common ability to induce the production of IL-1β by immune cells in vitro. Background/Rationale: IL-1β is an initiator cytokine that plays a central role in the regulation of immune and inflammatory responses. It is produced by activated macrophages and epithelial cells and requires two distinct signals for its synthesis, processing, and secretion. The first signal is mediated by p38 MAPK and results in the production of the 35 kDa pro-IL-1β a biologically inactive precursor of IL-1β. The second signal induces the processing of pro-IL-1β to the mature, 17 kDa biologically active IL-1β via the assembly of a multiprotein complex called the NLRP3 inflammasome. Doxorubicin, an anthracycline, stimulates the production of IL-1β in murine bone marrow derived macrophages (BMDM) in vitro by activating MAPK signaling and formation of the NLRP3 inflammasome. In vivo administration of doxorubicin in mice caused an increase in serum levels of IL-1β. In a mouse model of CTRS, a doxorubicin containing breast cancer chemotherapy regimen induced lethargy/ fatigue, weight loss, and anorexia, and peak symptoms were associated with systemic increases in IL-1b. Methods: BMDM were exposed to clinically relevant concentrations of cisplatin (platinum compound), vincristine (mitotic inhibitor), or etoposide (topoisomerase inhibitor) for 12-hours hours. Cell lysates and culture media were analyzed for activation of p38 MAPK, pro-IL-1β and mature IL-1β. Results: Like doxorubicin, cisplatin, vincristine, and etoposide were able to activate the MAPK signaling pathway as evidenced by increased levels of phosphorylated p38 MAPK in drug treated cells relative to untreated control cells. Increased activation of p38 MAPK was associated with increased expression of pro-IL-1β. All of the drugs tested were also capable of inducing the formation of the NLRP3 inflammasome resulting in the processing of cellular pro-IL-1β to mature IL-1β which could be observed in the culture medium. Implications: Our in vitro data show that mechanistically distinct cancer chemotherapeutic agents trigger the production of biologically active IL-1β by immune cells. In vivo experiments are needed to determine whether blockade of MAPK signaling or formation of the NLRP3 inflammasome are feasible approaches to preventing or managing CTRS. Understanding whether cytotoxic chemotherapeutic agents trigger CTRS via a shared mechanism will facilitate the development of therapeutic strategies aimed at preventing or managing CTRS in the clinical setting.
Keywords:
Cancer patients; Cancer treatment; Symptoms
Repository Posting Date:
20-Feb-2012
Date of Publication:
20-Feb-2012
Other Identifiers:
5481
Sponsors:
Western Institute of Nursing

Full metadata record

DC FieldValue Language
dc.typeResearch Studyen_GB
dc.titleCYTOTOXIC CANCER CHEMOTHERAPEUTIC AGENTS INDUCE IL-1β PRODUCTION BY IMMUNE CELLSen_GB
dc.identifier.urihttp://hdl.handle.net/10755/211560-
dc.description.abstractPurpose: Cancer patients treated with mechanistically distinct cytotoxic chemotherapeutic agents often experience a cluster of symptoms including, fatigue, lethargy, decreased appetite, sleep disturbance, difficulty thinking, and pain. These symptoms have a profound negative effect on physical functioning and quality of life (QOL). Our research group proposes that CTRS: (i) are mechanistically understandable at molecular and cellular levels and (ii) the onset and severity of CTRS are amenable for therapeutic modulation. It has long been recognized that these symptoms are remarkably similar to those associated with sickness behavior, a normal physiological response to activation of the innate immune system, in which pro-inflammatory cytokines such as IL-1β play a central role. The purpose of the present study is to determine whether cytotoxic chemotherapeutic agents from a variety of drug classes share a common ability to induce the production of IL-1β by immune cells in vitro. Background/Rationale: IL-1β is an initiator cytokine that plays a central role in the regulation of immune and inflammatory responses. It is produced by activated macrophages and epithelial cells and requires two distinct signals for its synthesis, processing, and secretion. The first signal is mediated by p38 MAPK and results in the production of the 35 kDa pro-IL-1β a biologically inactive precursor of IL-1β. The second signal induces the processing of pro-IL-1β to the mature, 17 kDa biologically active IL-1β via the assembly of a multiprotein complex called the NLRP3 inflammasome. Doxorubicin, an anthracycline, stimulates the production of IL-1β in murine bone marrow derived macrophages (BMDM) in vitro by activating MAPK signaling and formation of the NLRP3 inflammasome. In vivo administration of doxorubicin in mice caused an increase in serum levels of IL-1β. In a mouse model of CTRS, a doxorubicin containing breast cancer chemotherapy regimen induced lethargy/ fatigue, weight loss, and anorexia, and peak symptoms were associated with systemic increases in IL-1b. Methods: BMDM were exposed to clinically relevant concentrations of cisplatin (platinum compound), vincristine (mitotic inhibitor), or etoposide (topoisomerase inhibitor) for 12-hours hours. Cell lysates and culture media were analyzed for activation of p38 MAPK, pro-IL-1β and mature IL-1β. Results: Like doxorubicin, cisplatin, vincristine, and etoposide were able to activate the MAPK signaling pathway as evidenced by increased levels of phosphorylated p38 MAPK in drug treated cells relative to untreated control cells. Increased activation of p38 MAPK was associated with increased expression of pro-IL-1β. All of the drugs tested were also capable of inducing the formation of the NLRP3 inflammasome resulting in the processing of cellular pro-IL-1β to mature IL-1β which could be observed in the culture medium. Implications: Our in vitro data show that mechanistically distinct cancer chemotherapeutic agents trigger the production of biologically active IL-1β by immune cells. In vivo experiments are needed to determine whether blockade of MAPK signaling or formation of the NLRP3 inflammasome are feasible approaches to preventing or managing CTRS. Understanding whether cytotoxic chemotherapeutic agents trigger CTRS via a shared mechanism will facilitate the development of therapeutic strategies aimed at preventing or managing CTRS in the clinical setting.en_GB
dc.subjectCancer patientsen_GB
dc.subjectCancer treatmenten_GB
dc.subjectSymptomsen_GB
dc.date.available2012-02-20T12:02:20Z-
dc.date.issued2012-02-20T12:02:20Z-
dc.date.accessioned2012-02-20T12:02:20Z-
dc.description.sponsorshipWestern Institute of Nursingen_GB
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