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

• Published in: Science (American Association for the Advancement of Science) Vol. 281; no. 5379; pp. 1001 - 1005
• Main Authors: Carballo, Ester, Lai, Wi S., Blackshear, Perry J.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 14.08.1998; American Association for the Advancement of Science
• Subjects: 3T3 Cells; Animals; Antibodies; Bacteriophages; Base Sequence; Biological and medical sciences; Biological Transport; Cell Line; Cell lines; Cell Nucleus - metabolism; Cellular signal transduction; Chick Embryo; Complementary DNA; Cytosol; Cytosol - metabolism; DNA-Binding Proteins; Feedback; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation; Genomics; Humans; Immediate-Early Proteins; Inflammation; Lipopolysaccharides - pharmacology; Macrophages; Macrophages - physiology; Messenger RNA; Mice; Mice, Knockout; Molecular and cellular biology; Plasmids; Proteins - physiology; RNA; RNA Probes; RNA, Messenger - chemistry; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transfection; Tristetraprolin; Tumor necrosis factor; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Zinc Fingers; Stability; Cytokine; Rodentia; Inflammation; Gene expression; Vertebrata; Regulation(control); Mammalia; Messenger RNA; Gene; Mouse; Tumor; Mutation; Tumor necrosis factor α; Macrophage
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.281.5379.1001

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.