The tumor necrosis factor (TNF) gene is activated by multiple extracellular signals in a stimulus- and cell type-specific fashion. Based on the presence of κB-like DNA motifs in the region upstream of the TNF gene, some have proposed a direct role for NF-κB in lipopolysaccharide (LPS)-induced TNF gene transcription in cells of the monocyte/macrophage lineage. However, we have previously demonstrated a general and critical role for a minimal TNF promoter region bearing only one of the κB-like motifs, κ3, which is bound by nuclear factor of activated T cell proteins in lymphocytes and fibroblasts in response to multiple stimuli and Ets proteins in LPS-stimulated macrophages. Here, in an effort to resolve these contrasting findings, we used a combination of site-directed mutagenesis of the TNF promoter, quantitative DNase I footprinting, and analysis of endogenous TNF mRNA production in response to multiple stimuli under conditions that inhibit NF-κB activation (using the proteasome inhibitor lactacystin and using cells lacking either functional NF-κB essential modulator, which is the IκB kinase regulatory subunit, or the Nemo gene itself). We find that TNF mRNA production in response to ionophore is NF-κB-independent, but inhibition of NF-κB activation attenuates virus- and LPS-induced TNF mRNA levels after initial induction. We conclude that induction of TNF gene transcription by virus or LPS does not depend upon NF-κB binding to the proximal promoter; rather, a stimulus-specific post-induction mechanism involving NF-κB, yet to be characterized, is involved in the maintenance of maximal TNF mRNA levels.
Post-induction, Stimulus-specific Regulation of Tumor Necrosis Factor mRNA Expression*
A. Tsytsykova,J. Falvo,M. Schmidt-Supprian,G. Courtois,D. Thanos,A. Goldfeld
Published 2007 in Journal of Biological Chemistry
ABSTRACT
PUBLICATION RECORD
- Publication year
2007
- Venue
Journal of Biological Chemistry
- Publication date
2007-04-20
- Fields of study
Biology, Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- ionophore
A stimulus used to induce TNF mRNA production in the reported experiments.
- lipopolysaccharide (lps)
A bacterial stimulus used to trigger TNF expression in macrophage-lineage cells.
Aliases: LPS, lipopolysaccharide
- nf-κb
A transcription factor family examined for its role in regulating TNF expression.
Aliases: nuclear factor kappa B, NF-kappaB
- nf-κb activation
The signaling-dependent activation state of NF-κB that is experimentally inhibited in the study.
Aliases: activation of NF-κB
- post-induction mechanism
A regulatory mechanism acting after initial induction to sustain TNF expression.
Aliases: maintenance mechanism after induction
- proximal tnf promoter
The upstream TNF promoter region containing κB-like motifs that was analyzed by mutagenesis and footprinting.
Aliases: TNF promoter proximal region, proximal promoter
- tnf mrna levels
The measured abundance of endogenous TNF transcripts used as the expression readout.
Aliases: TNF mRNA production, TNF transcript levels
- tumor necrosis factor (tnf) gene
The gene studied here for stimulus-specific transcriptional regulation and mRNA output.
Aliases: TNF gene
- virus stimulus
A viral induction condition used to stimulate TNF mRNA production in the experiments.
Aliases: virus, viral stimulus
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