Abstract
The mechanisms by which thymosin β 4 (Tβ(4)) regulates the inflammatory response to injury are poorly understood. Previously, we demonstrated that ectopic Tβ(4) treatment inhibits injury-induced proinflammatory cytokine and chemokine production. We have also shown that Tβ(4) suppresses TNF-α-mediated NF-κB activation. Herein, we present novel evidence that Tβ(4) directly targets the NF-κB RelA/p65 subunit. We find that enforced expression of Tβ(4) interferes with TNF-α-mediated NF-κB activation, as well as downstream IL-8 gene transcription. These activities are independent of the G-actin-binding properties of Tβ(4). Tβ(4) blocks RelA/p65 nuclear translocation and targeting to the cognate κB site in the proximal region of the IL-8 gene promoter. Tβ(4) also inhibits the sensitizing effects of its intracellular binding partners, PINCH-1 and ILK, on NF-κB activity after TNF-α stimulation. The identification of a functional regulatory role by Tβ(4) and the focal adhesion proteins PINCH-1 and ILK on NF-κB activity in this study opens a new window for scientific exploration of how Tβ(4) modulates inflammation. In addition, the results of this study serve as a foundation for developing Tβ(4) as a new anti-inflammatory therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Actins / metabolism
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Adaptor Proteins, Signal Transducing
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Animals
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Anti-Inflammatory Agents / pharmacology
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COS Cells
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Cells, Cultured
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Chlorocebus aethiops
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Humans
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Interleukin-8 / antagonists & inhibitors
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Interleukin-8 / genetics
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Interleukin-8 / metabolism*
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LIM Domain Proteins
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Membrane Proteins
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Mutation
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Protein Binding
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Rats
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Thymosin / genetics
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Thymosin / pharmacology*
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Thymosin / physiology
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Transcription Factor RelA / antagonists & inhibitors
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Transcription Factor RelA / genetics
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Transcription Factor RelA / metabolism
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
Substances
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Actins
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Adaptor Proteins, Signal Transducing
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Anti-Inflammatory Agents
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DNA-Binding Proteins
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Interleukin-8
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LIM Domain Proteins
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LIMS1 protein, human
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Membrane Proteins
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NF-kappa B
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha
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thymosin beta(4)
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Thymosin
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integrin-linked kinase
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Protein Serine-Threonine Kinases