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
Section snippets
Background
Cancer patients undergoing treatment with cytotoxic chemotherapy often experience a cluster of symptoms including fatigue, loss of appetite (anorexia), sleep disturbance, pain, and cognitive dysfunction, which can have profound negative effects on physical functioning and quality of life during and after treatment (Berger et al., 2012, Oh and Seo, 2011). Cancer treatment related symptoms (CTRS) typically occur in the days following chemotherapy infusion (de Jong et al., 2005, de Jong et al.,
Mice
All animal procedures were performed according to protocols approved by the Institutional Animal Care and Use Committee at Oregon Health & Science University. Female mice lacking the interleukin-1 beta type 1 receptor (IL1R1: B6.129S7-Il1r1tm1Imx), and both IL1R1 and tumor necrosis factor alpha p55 (type 1) receptor (TNFR1: B6;129S-Tnfrsf1atm1Imx Il1r1tm1Imx/J), and genetically matched wild type (WT) control mice were purchased from Jackson Laboratories (Bar Harbor, ME). Mice for CTRS
Cytotoxic chemotherapy causes systemic increases in IL-1β and TNF-α
LPS administration in rodents causes a rapid and systemic increase in IL-1β and TNF-α expression that coincides with the onset of sickness behavior. We hypothesized that cytotoxic chemotherapy triggers a similar systemic response when injected into mice. To test this hypothesis we injected mice with CAF or NS and at 1- and/or, 3-, 6-, 14-, and 24-h post-injection collected peripheral blood, liver, spleen, hypothalamus and cerebellum (24-h time point only) from each mouse. Fig. 1A shows fold
Discussion
Although there have been studies examining the behavioral effects of cytotoxic chemotherapy in mice to our knowledge the present study is the first to examine the relationship between daily patterns of CTRS and inflammatory signaling in mice administered multiple doses of a multi-drug regimen over a clinically relevant time frame (i.e. 2–3 weeks). Using this clinically relevant approach we observed a distinct pattern of CTRS that was remarkably similar to that of cancer patients undergoing
Conclusions
Although our data further support a relationship between cytotoxic chemotherapy, pro-inflammatory signaling and CTRS, it suggests that one purpose of the chemotherapy induced acute inflammatory response, at least in the periphery, is the recovery from exposure to cytotoxic agents.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
L.J.W. conceived of and designed the study. L.J.W., L.B.S., C.A., and T.J.W. performed the experiments. M.C.L. and L.J.W. performed the statistical tests. L.J.W., L.B.S., and K.W. drafted the manuscript and figures. All authors read and approved the final manuscript.
Acknowledgments
We would like to thank Collin Elsea of Oregon Health & Science University for assistance with the RT-PCR experiments and the animal work. Funding for this study was provided by NINR R01NR012479 to L.J.W.
References (48)
- et al.
Cancer-related inflammation: common themes and therapeutic opportunities
Semin. Cancer Biol.
(2012) - et al.
Recovery of running performance following muscle-damaging exercise: relationship to brain IL-1beta
Brain Behav. Immun.
(2005) - et al.
Course of mental fatigue and motivation in breast cancer patients receiving adjuvant chemotherapy
Ann. Oncol.
(2005) - et al.
Cytokines as mediators of depression: what can we learn from animal studies?
Neurosci. Biobehav. Rev.
(2005) - et al.
Effects of 5-fluorouracil chemotherapy on fatigue: role of MCP-1
Brain Behav. Immun.
(2013) - et al.
Induction of interleukin-1 in various brain regions after peripheral and central injections of lipopolysaccharide
J. Neuroimmunol.
(1994) - et al.
Chemotherapy-induced anorexia is accompanied by activation of brain pathways signaling dehydration
Physiol. Behav.
(2010) - et al.
The changes induced by cyclophosphamide in intestinal barrier and microflora in mice
Eur. J. Pharmacol.
(2013) - et al.
Recombinant human interleukin-1 receptor antagonist protects mice against acute doxorubicin-induced cardiotoxicity
Eur. J. Pharmacol.
(2010) - et al.
In vitro and in vivo activity and pathophysiology of human interleukin-8 and related peptides
Int. Rev. Exp. Pathol.
(1993)
Cancer-related anemia
Saudi Med. J.
Vertebrate sickness behaviors: adaptive and integrated neuroendocrine immune responses
Integr. Comp. Biol.
Mechanism of cytokine modulation of epithelial tight junction barrier
Front. Biosci. (Landmark Ed)
Application of distance matrices to define associations between acute toxicities in colorectal cancer patients receiving chemotherapy
Cancer
Cytokines in the pathogenesis of cancer cachexia
Curr. Opin. Clin. Nutr. Metab. Care
Expression and regulation of the CXC-chemokines, GRO/KC and IP-10/mob-1 in rat seminiferous tubules
Eur. Cytokine Netw.
Cancer-related fatigue: implications for breast cancer survivors
Cancer
DAMPs, PAMPs and alarmins: all we need to know about danger
J. Leukoc. Biol.
Role of interleukin-1beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice
Eur. J. Neurosci.
Fatigue in long-term breast carcinoma survivors: a longitudinal investigation
Cancer
Experimental human endotoxemia: a model of the systemic inflammatory response syndrome?
Surg. Infect. (Larchmt)
Effects of granulocyte-colony stimulating factor on peritoneal defense mechanisms and bacterial translocation after administration of systemic chemotherapy in rats
World J. Gastroenterol.
Translational approaches to treatment-induced symptoms in cancer patients
Nat. Rev. Clin. Oncol.
Course of fatigue between two cycles of adjuvant chemotherapy in breast cancer patients
Cancer Nurs.
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