Nuclear factor-κB-dependent induction of interleukin-8 gene expression by tumor necrosis factor α: Evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation

Spiros Vlahopoulos, Istvan Boldogh, Antonella Casola, Allan R. Brasier

Research output: Contribution to journalArticle

188 Scopus citations

Abstract

Tumor necrosis factor α (TNFα) is a pluripotent activator of inflammation by inducing a proinflammatory cytokine cascade. This phenomenon is mediated, in part, through inducible expression of the CXC chemokine, interleukin-8 (IL-8). In this study, we investigate the role of TNFα- inducible reactive oxygen species (ROS) in IL-8 expression by 'monocyte-like' U937 histiocytic lymphoma cells. TNFα is a rapid activator of IL-8 gene expression by U937, producing a 50-fold induction of mRNA within 1 hour of treatment. In gene transfection assays, the effect of TNFα requires the presence of an inducible nuclear factor-κB (NF-κB) (Rel A) binding site in the IL-8 promoter. TNFα treatment induces a rapid translocation of the 65 kD transcriptional activator NF-κB subunit, Rel A, whose binding in the nucleus occurs before changes in intracellular ROS. Pretreatment (or up to 15 minutes posttreatment) relative to TNFα with the antioxidant dimethyl sulfoxide (DMSO) (2% [vol/vol]) blocks 80% of NF-κB-dependent transcription. Surprisingly, however, DMSO has no effect on inducible Rel A binding. Similar selective effects on NF-κB transcription are seen with the unrelated antioxidants, N-acetylcysteine (NAC) and vitamin C. These data indicate that TNFα induces a delayed ROS-dependent signalling pathway that is required for NF-κB transcriptional activation and is separable from that required for its nuclear translocation. Further definition of this pathway will yield new insights into inflammation initiated by TNFα signalling.

Original languageEnglish (US)
Pages (from-to)1878-1889
Number of pages12
JournalBlood
Volume94
Issue number6
StatePublished - Sep 15 1999

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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