Integrin-mediated activation of transforming growth factor-beta(1) in pulmonary fibrosis

The integrin alphav beta6 is restricted to epithelial cells and is dramatic ally induced in response to injury and inflammation. Mice expressing a null mutation of this integrin develop exaggerated inflammation of the lungs an d skin, but are dramatically protected from bleomycin-induced pulmonary fib rosis. This phenotype led to the identification of a unique role for this i ntegrin in binding to and activating latent extracellular complexes of the anti-inflammatory, profibrotic cytokine, transforming growth factor-beta (1 ). This integrin-mediated activation is tightly spatially restricted and ap pears to require direct presentation of the activated cytokine to receptors on adjacent cells. The process also requires distinct regions of the beta6 -subunit cytoplasmic domain and an intact actin cytoskeleton, suggesting th e existence of additional cellular mechanisms to regulate this process. If this mechanism is found to be as important in humans as it is in mice, the integrin and as yet to be identified pathways for cellular regulation of th is process could be exciting new targets for intervention in fibrotic disea ses of the lung and other epithelial organs.