Integrin-Mediated Transforming Growth Factor-β Activation, a Potential Therapeutic Target in Fibrogenic Disorders

Transcription of the Transforming Growth Factor β Activating Integrin β8 Subunit Is Regulated by SP3, AP-1, and the p38 Pathway

“…Previous studies have demonstrated important roles for AP-1, p38, and TGF-␤ in normal epithelial-mesenchymal homeostasis and wound healing of the skin and lung (23,47,84,85). We have also shown that integrin ␤8 regulates epithelial-mesenchymal and endothelial-mesenchymal homeostasis in the airway and brain, respectively (1,2,15,17).…”

“…TGF-␤ is a crucial mediator of immune and epithelial-mesenchymal homeostasis through diverse effects on cellular differentiation, proliferation, and apoptosis (23). Previous studies have demonstrated important roles for AP-1, p38, and TGF-␤ in normal epithelial-mesenchymal homeostasis and wound healing of the skin and lung (23,47,84,85).…”

“…Thus, ␣v␤8 is a major "gatekeeper" of TGF-␤ function. Most of the functions of ␣v␤8, in vivo, including vascular differentiation (17), airway fibrosis in chronic obstructive pulmonary disease (1,23,29), cancer cell proliferation (4), and metastasis (19) have been attributed to ␣v␤8-mediated activation of TGF␤.…”

“…The main, if not the only, physiologically relevant ligand for integrin ␣v␤8 is transforming growth factor ␤ (TGF-␤), 3 a multifunctional cytokine that regulates cell proliferation, differentiation, survival, matrix synthesis, and immune cell function (23). TGF-␤ is ubiquitously expressed in three isoforms in mammals (TGF-␤ 1-3), but is maintained in an inactive form by its non-covalent interaction with its propeptide, the latency associated peptide of TGF-␤ (24).…”

Integrins in Wound Healing

“…However, some therapies targeting a v b 6 integrin are being developed that show promise in reducing fibrosis. 4 In addition, transferring oral cells to an extra-oral location to improve healing outcomes has been proposed. 5 …”