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The role of IL-1? and TNF-? 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-1? and TNF-? 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-? p55 (type 1) receptor (TNFR1-/-) and/or IL-1? 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-1? and TNF-? 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-1? and TNF-? driven inflammatory cascade is to promote recovery following exposure to cytotoxic agents.

SUBMITTER: Smith LB

PROVIDER: S-EPMC3989411 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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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.

Smith Logan B LB Leo Michael C MC Anderson Caroline C Wright Teresa J TJ Weymann Kristianna B KB Wood Lisa J LJ

Brain, behavior, and immunity 20140108

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 cyc ...[more]

PMID: 24412646

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Project description:Adipose tissue-derived stem cell (ADSC) transplantation has been shown to be effective for the management of severe liver disorders. Preactivation of ADSCs enhanced their therapeutic efficacy. However, these effects have not yet been examined in relation to cholestatic liver injury. In the present study, a cholestatic liver injury model was established by bile duct ligation (BDL) in male C57BL/6 mice. Human ADSCs (hADSCs) with or without tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) pretreatment were administrated into the mice via tail vein injections. The efficacy of hADSCs on BDL-induced liver injury was assessed by histological staining, real-time quantitative PCR (RT-qPCR), Western blot, and enzyme-linked immune sorbent assay (ELISA). In vitro, the effects of hADSC conditioned medium on the activation of hepatic stellate cells (HSCs) were investigated. Small interfering RNA (siRNA) was used to knock down cyclooxygenase-2 (COX-2) in hADSCs. TNF-α/IL-1β preconditioning could downregulate immunogenic gene expression and enhance the engraftment efficiency of hADSCs. Compared to control hADSCs (C-hADSCs), TNF-α/IL-1β-pretreated hADSCs (P-hADSCs) significantly alleviated BDL-induced liver injury, as demonstrated by reduced hepatic cell death, attenuated infiltration of Ly6G + neutrophils, and decreased expression of pro-inflammatory cytokines TNF-α, IL-1β, C-X-C motif chemokine ligand 1 (CXCL1), and C-X-C motif chemokine ligand 2 (CXCL2). Moreover, P-hADSCs significantly delayed the development of BDL-induced liver fibrosis. In vitro, conditioned medium from P-hADSCs significantly inhibited HSC activation compared to that from C-hADSCs. Mechanistically, TNF-α/IL-1β upregulated COX-2 expression and increased prostaglandin E2 (PGE2) secretion. The blockage of COX-2 by siRNA transfection reversed the benefits of P-hADSCs for PGE2 production, HSC activation, and liver fibrosis progression. In conclusion, our results suggest that TNF-α/IL-1β pretreatment enhances the efficacy of hADSCs in mice with cholestatic liver injury, partially through the COX-2/PGE2 pathway.

Dataset Information

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

Publications

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.

Similar Datasets

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