title: 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 3weeks 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.
authors.affiliation: School of Nursing, Oregon Health Science University, Portland, OR 97239, United States. Electronic address: loganblairsmith@gmail.com.
authors.forename: Logan B
authors.initials: LB
authors.lastname: Smith
authors.affiliation: Center for Health Research, Kaiser Permanente Northwest, Portland, OR 97227, United States. Electronic address: Michael.C.Leo@kpchr.org.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Leo
authors.affiliation: School of Nursing, Oregon Health Science University, Portland, OR 97239, United States. Electronic address: andcarol@ohsu.edu.
authors.forename: Caroline
authors.initials: C
authors.lastname: Anderson
authors.affiliation: School of Nursing, Oregon Health Science University, Portland, OR 97239, United States. Electronic address: twright186@gmail.com.
authors.forename: Teresa J
authors.initials: TJ
authors.lastname: Wright
authors.affiliation: School of Nursing, Oregon Health Science University, Portland, OR 97239, United States. Electronic address: weymannk@ohsu.edu.
authors.forename: Kristianna B
authors.initials: KB
authors.lastname: Weymann
authors.affiliation: School of Nursing, Oregon Health Science University, Portland, OR 97239, United States. Electronic address: ljwood@mghihp.edu.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Wood
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000633:toxicity*; D003520:Cyclophosphamide / Q000633:toxicity; D004317:Doxorubicin / Q000633:toxicity; D005260:Female; D005472:Fluorouracil / Q000633:toxicity; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018121:Receptors, Cytokine / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D018121:Receptors, Cytokine; D053573:Receptors, Interleukin-1 Type I; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D003520:Cyclophosphamide; D005472:Fluorouracil
keywords: Cancer related fatigue; IL-1β; Sickness behavior; TNF-α