The role of tumour necrosis factor-α and tumour necrosis factor receptor signalling in inflammation-associated systemic genotoxicity

Aya M. Westbrook, Bo Wei, Katrin Hacke, Menghang Xia, Jonathan Braun, Robert H. Schiestl

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Chronic inflammatory diseases are characterised by systemically elevated levels of tumour necrosis factor (TNF)-α, a proinflammatory cytokine with pleiotropic downstream effects. We have previously demonstrated increased genotoxicity in peripheral leukocytes and various tissues in models of intestinal inflammation. In the present study, we asked whether TNF-α is sufficient to induce DNA damage systemically, as observed in intestinal inflammation, and whether tumour necrosis factor receptor (TNFR) signalling would be necessary for the resultant genotoxicity. In the wild-type mice, 500 ng per mouse of TNF-α was sufficient to induce DNA damage to multiple cell types and organs 1-h post-administration. Primary splenic T cells manifested TNF-α-induced DNA damage in the absence of other cell types. Furthermore, TNFR1 -/-TNFR2 -/- mice demonstrated decreased systemic DNA damage in a model of intestinal inflammation and after TNF-α injection versus wild-type mice, indicating the necessity of TNFR signalling. Nuclear factor (NF)-κB inhibitors were also able to decrease damage induced by TNF-α injection in wild-type mice. When TNF-α administration was combined with interleukin (IL)-1β, another proinflammatory cytokine, DNA damage persisted for up to 24 h. When combined with IL-10, an anti-inflammatory cytokine, decreased genotoxicity was observed in vivo and in vitro. TNF-α/TNFR-mediated signalling is therefore sufficient and plays a large role in mediating DNA damage to various cell types, subject to modulation by other cytokines and their mediators.

Original languageEnglish (US)
Pages (from-to)77-86
Number of pages10
JournalMutagenesis
Volume27
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

Fingerprint

Tumor Necrosis Factor Receptors
Tumor Necrosis Factor-alpha
DNA Damage
Inflammation
DNA
Cytokines
Receptors, Tumor Necrosis Factor, Type II
Receptors, Tumor Necrosis Factor, Type I
Injections
T-cells
Interleukin-1
Interleukin-10
Leukocytes
Chronic Disease
Anti-Inflammatory Agents
Modulation
Tissue
T-Lymphocytes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

The role of tumour necrosis factor-α and tumour necrosis factor receptor signalling in inflammation-associated systemic genotoxicity. / Westbrook, Aya M.; Wei, Bo; Hacke, Katrin; Xia, Menghang; Braun, Jonathan; Schiestl, Robert H.

In: Mutagenesis, Vol. 27, No. 1, 01.2012, p. 77-86.

Research output: Contribution to journalArticle

Westbrook, Aya M. ; Wei, Bo ; Hacke, Katrin ; Xia, Menghang ; Braun, Jonathan ; Schiestl, Robert H. / The role of tumour necrosis factor-α and tumour necrosis factor receptor signalling in inflammation-associated systemic genotoxicity. In: Mutagenesis. 2012 ; Vol. 27, No. 1. pp. 77-86.
@article{875d65f25eee4a61a880c8f083bc3abe,
title = "The role of tumour necrosis factor-α and tumour necrosis factor receptor signalling in inflammation-associated systemic genotoxicity",
abstract = "Chronic inflammatory diseases are characterised by systemically elevated levels of tumour necrosis factor (TNF)-α, a proinflammatory cytokine with pleiotropic downstream effects. We have previously demonstrated increased genotoxicity in peripheral leukocytes and various tissues in models of intestinal inflammation. In the present study, we asked whether TNF-α is sufficient to induce DNA damage systemically, as observed in intestinal inflammation, and whether tumour necrosis factor receptor (TNFR) signalling would be necessary for the resultant genotoxicity. In the wild-type mice, 500 ng per mouse of TNF-α was sufficient to induce DNA damage to multiple cell types and organs 1-h post-administration. Primary splenic T cells manifested TNF-α-induced DNA damage in the absence of other cell types. Furthermore, TNFR1 -/-TNFR2 -/- mice demonstrated decreased systemic DNA damage in a model of intestinal inflammation and after TNF-α injection versus wild-type mice, indicating the necessity of TNFR signalling. Nuclear factor (NF)-κB inhibitors were also able to decrease damage induced by TNF-α injection in wild-type mice. When TNF-α administration was combined with interleukin (IL)-1β, another proinflammatory cytokine, DNA damage persisted for up to 24 h. When combined with IL-10, an anti-inflammatory cytokine, decreased genotoxicity was observed in vivo and in vitro. TNF-α/TNFR-mediated signalling is therefore sufficient and plays a large role in mediating DNA damage to various cell types, subject to modulation by other cytokines and their mediators.",
author = "Westbrook, {Aya M.} and Bo Wei and Katrin Hacke and Menghang Xia and Jonathan Braun and Schiestl, {Robert H.}",
year = "2012",
month = "1",
doi = "10.1093/mutage/ger063",
language = "English (US)",
volume = "27",
pages = "77--86",
journal = "Mutagenesis",
issn = "0267-8357",
publisher = "Oxford University Press",
number = "1",

}

TY - JOUR

T1 - The role of tumour necrosis factor-α and tumour necrosis factor receptor signalling in inflammation-associated systemic genotoxicity

AU - Westbrook, Aya M.

AU - Wei, Bo

AU - Hacke, Katrin

AU - Xia, Menghang

AU - Braun, Jonathan

AU - Schiestl, Robert H.

PY - 2012/1

Y1 - 2012/1

N2 - Chronic inflammatory diseases are characterised by systemically elevated levels of tumour necrosis factor (TNF)-α, a proinflammatory cytokine with pleiotropic downstream effects. We have previously demonstrated increased genotoxicity in peripheral leukocytes and various tissues in models of intestinal inflammation. In the present study, we asked whether TNF-α is sufficient to induce DNA damage systemically, as observed in intestinal inflammation, and whether tumour necrosis factor receptor (TNFR) signalling would be necessary for the resultant genotoxicity. In the wild-type mice, 500 ng per mouse of TNF-α was sufficient to induce DNA damage to multiple cell types and organs 1-h post-administration. Primary splenic T cells manifested TNF-α-induced DNA damage in the absence of other cell types. Furthermore, TNFR1 -/-TNFR2 -/- mice demonstrated decreased systemic DNA damage in a model of intestinal inflammation and after TNF-α injection versus wild-type mice, indicating the necessity of TNFR signalling. Nuclear factor (NF)-κB inhibitors were also able to decrease damage induced by TNF-α injection in wild-type mice. When TNF-α administration was combined with interleukin (IL)-1β, another proinflammatory cytokine, DNA damage persisted for up to 24 h. When combined with IL-10, an anti-inflammatory cytokine, decreased genotoxicity was observed in vivo and in vitro. TNF-α/TNFR-mediated signalling is therefore sufficient and plays a large role in mediating DNA damage to various cell types, subject to modulation by other cytokines and their mediators.

AB - Chronic inflammatory diseases are characterised by systemically elevated levels of tumour necrosis factor (TNF)-α, a proinflammatory cytokine with pleiotropic downstream effects. We have previously demonstrated increased genotoxicity in peripheral leukocytes and various tissues in models of intestinal inflammation. In the present study, we asked whether TNF-α is sufficient to induce DNA damage systemically, as observed in intestinal inflammation, and whether tumour necrosis factor receptor (TNFR) signalling would be necessary for the resultant genotoxicity. In the wild-type mice, 500 ng per mouse of TNF-α was sufficient to induce DNA damage to multiple cell types and organs 1-h post-administration. Primary splenic T cells manifested TNF-α-induced DNA damage in the absence of other cell types. Furthermore, TNFR1 -/-TNFR2 -/- mice demonstrated decreased systemic DNA damage in a model of intestinal inflammation and after TNF-α injection versus wild-type mice, indicating the necessity of TNFR signalling. Nuclear factor (NF)-κB inhibitors were also able to decrease damage induced by TNF-α injection in wild-type mice. When TNF-α administration was combined with interleukin (IL)-1β, another proinflammatory cytokine, DNA damage persisted for up to 24 h. When combined with IL-10, an anti-inflammatory cytokine, decreased genotoxicity was observed in vivo and in vitro. TNF-α/TNFR-mediated signalling is therefore sufficient and plays a large role in mediating DNA damage to various cell types, subject to modulation by other cytokines and their mediators.

UR - http://www.scopus.com/inward/record.url?scp=84555188670&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84555188670&partnerID=8YFLogxK

U2 - 10.1093/mutage/ger063

DO - 10.1093/mutage/ger063

M3 - Article

C2 - 21980144

AN - SCOPUS:84555188670

VL - 27

SP - 77

EP - 86

JO - Mutagenesis

JF - Mutagenesis

SN - 0267-8357

IS - 1

ER -