Thymosin beta4 inhibits TNF-alpha-induced NF-kappaB activation, IL-8 expression, and the sensitizing effects by its partners PINCH-1 and ILK.

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.

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