Integrin-mediated activation of transforming growth factor-beta(1) in pulmonary fibrosis.
The integrin alphavbeta6 is restricted to epithelial cells and is dramatically induced in response to injury and inflammation. Mice expressing a null mutation of this integrin develop exaggerated inflammation of the lungs and skin, but are dramatically protected from bleomycin-induced pulmonary fibrosis. This phenotype led to the identification of a unique role for this integrin 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 appears 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 the 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 this process could be exciting new targets for intervention in fibrotic diseases of the lung and other epithelial organs.
Sheppard
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Lung Biology Center, Center for Occupational and Environmental Health, Cardiovascular Research Institute, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
D000818:Animals; D000951:Antigens, Neoplasm; D016023:Integrins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009154:Mutation; D011658:Pulmonary Fibrosis / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D000951:Antigens, Neoplasm; D016023:Integrins; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C073878:integrin alphavbeta6