Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin

Science. 1998 Aug 14;281(5379):1001-5. doi: 10.1126/science.281.5379.1001.


Tumor necrosis factor-alpha (TNF-alpha) is a major mediator of both acute and chronic inflammatory responses in many diseases. Tristetraprolin (TTP), the prototype of a class of Cys-Cys-Cys-His (CCCH) zinc finger proteins, inhibited TNF-alpha production from macrophages by destabilizing its messenger RNA. This effect appeared to result from direct TTP binding to the AU-rich element of the TNF-alpha messenger RNA. TTP is a cytosolic protein in these cells, and its biosynthesis was induced by the same agents that stimulate TNF-alpha production, including TNF-alpha itself. These findings identify TTP as a component of a negative feedback loop that interferes with TNF-alpha production by destabilizing its messenger RNA. This pathway represents a potential target for anti-TNF-alpha therapies.

MeSH terms

  • 3T3 Cells
  • Animals
  • Base Sequence
  • Biological Transport
  • Cell Line
  • Cell Nucleus / metabolism
  • Chick Embryo
  • Cytosol / metabolism
  • DNA-Binding Proteins*
  • Feedback
  • Gene Expression Regulation
  • Humans
  • Immediate-Early Proteins*
  • Lipopolysaccharides / pharmacology
  • Macrophages / physiology*
  • Mice
  • Mice, Knockout
  • Proteins / physiology*
  • RNA Probes
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transfection
  • Tristetraprolin
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / genetics
  • Zinc Fingers*


  • DNA-Binding Proteins
  • Immediate-Early Proteins
  • Lipopolysaccharides
  • Proteins
  • RNA Probes
  • RNA, Messenger
  • Tristetraprolin
  • Tumor Necrosis Factor-alpha
  • ZFP36 protein, human
  • Zfp36 protein, mouse