Feedback Inhibition of Macrophage Tumor Necrosis Factor-α Production by Tristetraprolin

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Science  14 Aug 1998:
Vol. 281, Issue 5379, pp. 1001-1005
DOI: 10.1126/science.281.5379.1001

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Tumor necrosis factor–α (TNF-α) 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-α 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-α messenger RNA. TTP is a cytosolic protein in these cells, and its biosynthesis was induced by the same agents that stimulate TNF-α production, including TNF-α itself. These findings identify TTP as a component of a negative feedback loop that interferes with TNF-α production by destabilizing its messenger RNA. This pathway represents a potential target for anti–TNF-α therapies.

  • * These authors contributed equally to this report.

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