The role of IL-1β and TNF-α signaling in the genesis of cancer treatment related symptoms (CTRS): A study using cytokine receptor-deficient mice

Abstract

Cytotoxic chemotherapeutic agents often induce a cluster of cancer treatment related symptoms (CTRS). The purpose of this study was to develop a mouse model of CTRS to examine the role of IL-1β and TNF-α signaling in the genesis of these symptoms. CTRS (change in wheel running activity, food intake, and body weight from baseline) were examined in wild type (WT) mice or mice lacking the TNF-α p55 (type 1) receptor (TNFR1−/−) and/or IL-1β type 1 receptor (IL-1R1−/−) injected with four doses of cyclophosphamide/Adriamycin/5-fluorouracil (CAF) at 20-day intervals. Inflammatory cytokines in blood and tissues were measured using multiplex immunoassays and quantitative RT-PCR. ANOVA was used to examine differences between genotype and/or treatment group. Kaplan-Meier analysis was used to estimate survival rate. CAF rapidly increased IL-1β and TNF-α signaling in WT mice. CAF induced acute CTRS immediately following drug injection which returned to baseline prior to the next CAF dose. Persistent CTRS were evident 3 weeks after the 4th CAF dose. Acute but not persistent CTRS were associated with increased levels of IL-7, IL-9, KC, MCP-1, GCSF, and IP-10. This CAF induced inflammatory response was blunted in IL-1R1 deficient mice and absent in IL-1R1/TNFR1-deficient mice. IL-1R1−/− mice showed an identical pattern of CTRS to their WT counterparts. The assessment of CTRS in IL-1R1/TNF-R1-deficient mice was precluded by severe toxicity. Our data suggest that an important function of the IL-1β and TNF-α driven inflammatory cascade is to promote recovery following exposure to cytotoxic agents.

Cytotoxic chemotherapy increases sleep and sleep fragmentation in non-tumor-bearing mice

“…Our data compliment and extend previous observations describing a 'fatigue' phenotype in mice following intra-peritoneal administration of cyclophosphamide, doxorubicin, and 5-fluorouracil Wood and Weymann, 2013;Smith et al, 2014). Due to logistical reasons and ease of measurement, most previous studies have administered chemotherapy into the peritoneal cavity (IP) and focused on fatigue independent of sleep; a potential confounding factor associated with this approach is that IP administration of doxorubicin causes diaphragm weakness (Gilliam et al, 2011), which in turn can exacerbate fatigue.…”

“…In this study, central cytokine expression was not examined further than 48 h following treatment. Recent evidence has emerged for a potential biphasic induction of central cytokine transcription following chemotherapy (Smith et al, 2014). The question of how this allostatic response to chemotherapy may affect sleep merits further research.…”

“…Many proinflammatory cytokines increase sleep and lethargy following peripheral immune activation (Krueger et al, 2001(Krueger et al, , 2011Opp, 2005). Previous studies have demonstrated that mice receiving doxorubicin, cyclophosphamide, and 5-fluorouracil have increased central inflammation and display a 'fatigue' phenotype (reduced voluntary wheel running behavior) that progressively worsens with each chemotherapy treatment Smith et al, 2014). Because increased cytokine expression can exert direct effects on sleep, in addition to fatigue, we assessed the acute effects of chemotherapy on sleep and sleep propensity in the present study.…”

Induction of IL-6 by Cytotoxic Chemotherapy Is Associated With Loss of Lean Body and Fat Mass in Tumor-free Female Mice

“…We previously developed a clinically relevant adjuvant breast cancer chemotherapy treatment model to determine the specific roles of inflammatory cytokines in the genesis of treatment-related symptoms in mice (Smith et al, 2014). Using this model, we showed that mice injected with four cycles of cytoxan-adriamycin-5-flourouracil (CAF) administered at 3-week intervals developed acute and persistent fatigue and weight loss.…”

Inflammatory Signaling in Post-Stroke Fatigue and Depression

“…The development of a clinically relevant animal model of PSF would facilitate future experiments. Development of such a model was critical for understanding the role of inflammatory signaling in the etiology of CTRF [53,116]. There have been only a handful of studies in which stroke-related immune changes were correlated to symptom severity in stroke survivors.…”