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

Logan B. Smith, Michael C. Leo, Caroline Anderson, Teresa J. Wright, Kristianna B. Weymann, Lisa J. Wood

Research output: Contribution to journalArticle

27 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)66-76
Number of pages11
JournalBrain, Behavior, and Immunity
StatePublished - May 2014



  • Cancer related fatigue
  • IL-1β
  • Sickness behavior
  • TNF-α

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

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