Thymosin β₄inhibits TNF‐α‐induced NF‐κB activation, IL‐8 expression, and the sensitizing effects by its partners PINCH‐1 and ILK

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.

Thymosin β4 induces proliferation, invasion, and epithelial-to-mesenchymal transition of oral squamous cell carcinoma

“…Also, Tβ4 interacts with the cytoplasmic domain of stabilin-2 and overexpression of Tβ4 increased the phagocytic activity of stabilin-2 (Lee et al 2008). Recently, novel evidence demonstrates that Tβ4 directly targets the NF-κB RelA/p65 subunit after TNF-α stimulation and inhibits the sensitizing effects of its intracellular binding partners, PINCH-1 and ILK (Qiu et al 2011). Therefore, it is needed that additional studies should elucidate interaction of Tβ4 and several binding partner in OSCCs.…”

Effects of thymosin β4 on a rat model of severe acute pancreatitis

“…As reviewed recently, thymosin β4 has clear anti-inflammatory and anti-septic shock activities (12,26). In addition, thymosin β4 can inhibit TNF-α-mediated NF-κB nuclear translocation and activation (15,16,27).…”

“…It has been shown to downregulate a number of key inflammatory mediators (e.g., IL-1β and TNF-α) and decreases the infiltration of inflammatory cells (11)(12)(13)(14). Thymosin β4 has also been found to reduce inflammation by inhibiting the activation of NF-κB in TNF-α-induced cells (15,16). A number of studies have suggested that thymosin β4 is capable of promoting new blood vessel formation via stimulating the differentiation and directional migration of endothelial cells (17,18).…”

Thymosin β4 promotes angiogenesis and increases muscle progenitor cell density in ischemic skeletal muscle in a mouse model of hind limb ischemia

“…In addition, Tβ4 has wound-healing and tissue-repair properties, which is associated with its ability to inhibit apoptosis and inflammation [5][6][7][8]. It can promote dermal healing in normal animals as well as in impaired models of dermal wound healing, including aged mice, diabetic mice, and steroid-treated rats [5].…”

“…It promotes corneal wound healing by topical treatment after an alkali injury [6]. Tβ4 inhibits polymorphonuclear leukocyte infiltration and suppresses the expression of interleukin proteins (IL-lβ and IL-8), chemokines, macrophage inflammatory protein (MIP-1α, MIP-1β, and MIP-2), and monocyte chemoattractant protein-1 (MCP-1) in corneal wound healing after an injury [7,8]. The anti-apoptotic properties displayed by Tβ4 is mediated by activating integrin-linked kinase (ILK), which results in activation of the survival kinase, Akt (also known as protein kinase B) [2].…”