Endotoxic shock in AUF1 knockout mice mediated by failure to degrade proinflammatory cytokine mRNAs

Jin Yu Lu, Navid Sadri, Robert J. Schneider

Research output: Contribution to journalArticlepeer-review

162 Scopus citations

Abstract

Excessive production of proinflammatory cytokines, particularly tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β), plays a critical role in septic shock induced by bacterial endotoxin (endotoxemia). Precise control of cytokine expression depends on rapid degradation of cytokine mRNAs, mediated by an AU-rich element (ARE) in the 3′ noncoding region and by interacting ARE-binding proteins, which control the systemic inflammatory response. To understand the function of the ARE-binding protein AUF1, we developed an AUF1 knockout mouse. We show that AUF1 normally functions to protect against the lethal progression of endotoxemia. Upon endotoxin challenge, AUF1 knockout mice display symptoms of severe endotoxic shock, including vascular hemorrhage, intravascular coagulation, and high mortality, resulting from overproduction of TNFα and IL-1β. Overexpression of these two cytokines is specific, and shown to result from an inability to rapidly degrade these mRNAs in macrophages following induction. Neutralizing antibodies to TNFα and IL-1β protect AUF1 knockout mice against lethal endotoxic shock. These and other data describe a novel post-transcriptional mechanism whereby AUF1 acts as a crucial attenuator of the inflammatory response, promoting the rapid decay of selective proinflammatory cytokine mRNAs following endotoxin activation. Defects in the AUF1 post-transcriptionally controlled pathway may be involved in human inflammatory disease.

Original languageEnglish (US)
Pages (from-to)3174-3184
Number of pages11
JournalGenes and Development
Volume20
Issue number22
DOIs
StatePublished - Nov 15 2006
Externally publishedYes

Keywords

  • ARE
  • AU-rich element
  • AUF1
  • Cytokines
  • Endotoxic shock
  • mRNA decay

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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