Mice that lack activity of alphavbeta6- and alphavbeta8-integrins reproduce the abnormalities of Tgfb1- and Tgfb3-null mice.
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.
Aluwihare
Poshala
P
Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
Mu
Zhenyu
Z
Zhao
Zhicheng
Z
Yu
Dawen
D
Weinreb
Paul H
PH
Horan
Gerald S
GS
Violette
Shelia M
SM
Munger
John S
JS
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D002972:Cleft Palate / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016023:Integrins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D007801:Langerhans Cells / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009842:Oligopeptides / Q000378:metabolism; D010159:Palate / Q000002:abnormalities* / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053782:Transforming Growth Factor beta3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D000951:Antigens, Neoplasm; D016023:Integrins; D009842:Oligopeptides; D053773:Transforming Growth Factor beta1; D053782:Transforming Growth Factor beta3; C073878:integrin alphavbeta6; C403414:integrin alphavbeta8; C047981:arginyl-glycyl-aspartic acid