The mechanisms by which thymosin β 4 (Tβ4) regulates the inflammatory response to injury are poorly understood. Previously, we demonstrated that ectopic Tβ4 treatment inhibits injury-induced proinflammatory cytokine and chemokine production. We have also shown that Tβ4 suppresses TNF-α-mediated NF-κB activation. Herein, we present novel evidence that Tβ4 directly targets the NF-κB RelA/p65 subunit. We find that enforced expression of Tβ4 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 Tβ4. Tβ4 blocks RelA/p65 nuclear translocation and targeting to the cognate κB site in the proximal region of the IL-8 gene promoter. Tβ4 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 Tβ4 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 Tβ4 modulates inflammation. In addition, the results of this study serve as a foundation for developing Tβ4 as a new anti-inflammatory therapy.—Qiu, P., Kurpakus Wheater, M., Qiu, Y., Sosne, G. Thymosin β4 inhibits TNF-α-induced NF-κB activation, IL-8 expression, and the sensitizing effects by its partners PINCH-1 and ILK
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