Abstract
The arginine-glycine-aspartate (RGD)-binding integrins alphavbeta6 and alphavbeta8 activate latent TGFbeta1 and TGFbeta3 in vivo, but it is uncertain whether other RGD-binding integrins such as integrins alphavbeta5 and alphavbeta3 activate these TGFbeta isoforms. To define the combined role of alphavbeta6- and alphavbeta8-integrin in TGFbeta activation, we analyzed mice lacking function of both integrins by means of gene deletion and/or pharmacologic inhibition. Most Itgb6-/-;Itgb8-/- embryos die at mid-gestation; those that survive develop cleft palate-as observed in Tgfb3-/- mice. Itgb8-/- mice treated with an anti-alphavbeta6-integrin antibody develop severe autoimmunity and lack Langerhans cells-similar to Tgfb1-null mice. These results support a model in which TGFbeta3-mediated palate fusion and TGFbeta1-mediated suppression of autoimmunity and generation of Langerhans cells require integrins alphavbeta6 and alphavbeta8 but not other RGD-binding integrins as TGFbeta activators.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / immunology
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Antigens, Neoplasm / metabolism*
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Autoimmunity / genetics
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Autoimmunity / immunology
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Cleft Palate / genetics
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Cleft Palate / immunology
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Cleft Palate / metabolism*
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Integrins / genetics
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Integrins / immunology
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Integrins / metabolism*
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Kaplan-Meier Estimate
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Langerhans Cells / immunology
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Mice
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Mice, Knockout
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Oligopeptides / metabolism
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Palate / abnormalities*
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Palate / immunology
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Palate / metabolism
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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Transforming Growth Factor beta1 / genetics
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Transforming Growth Factor beta1 / immunology
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Transforming Growth Factor beta1 / metabolism*
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Transforming Growth Factor beta3 / genetics
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Transforming Growth Factor beta3 / immunology
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Transforming Growth Factor beta3 / metabolism*
Substances
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Antigens, Neoplasm
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Integrins
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Oligopeptides
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Transforming Growth Factor beta1
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Transforming Growth Factor beta3
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integrin alphavbeta6
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integrin alphavbeta8
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arginyl-glycyl-aspartic acid