Abstract
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
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3T3 Cells
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Animals
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Base Sequence
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Biological Transport
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Cell Line
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Cell Nucleus / metabolism
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Chick Embryo
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Cytosol / metabolism
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DNA-Binding Proteins*
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Feedback
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Gene Expression Regulation
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Humans
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Immediate-Early Proteins*
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Lipopolysaccharides / pharmacology
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Macrophages / physiology*
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Mice
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Mice, Knockout
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Proteins / physiology*
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RNA Probes
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RNA, Messenger / chemistry
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Transfection
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Tristetraprolin
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / biosynthesis*
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Tumor Necrosis Factor-alpha / genetics
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Zinc Fingers*
Substances
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DNA-Binding Proteins
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Immediate-Early Proteins
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Lipopolysaccharides
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Proteins
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RNA Probes
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RNA, Messenger
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Tristetraprolin
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Tumor Necrosis Factor-alpha
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ZFP36 protein, human
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Zfp36 protein, mouse