Transforming growth factor-beta 1 modulates beta 1 and beta 5 integrin receptors and induces the de novo expression of the alpha v beta 6 heterodimer in normal human keratinocytes: implications for wound healing.
The molecular mechanism underlying the promotion of wound healing by TGF-beta 1 is incompletely understood. We report that TGF-beta 1 regulates the regenerative/migratory phenotype of normal human keratinocytes by modulating their integrin receptor repertoire. In growing keratinocyte colonies but not in fully stratified cultured epidermis, TGF-beta 1: (a) strongly upregulates the expression of the fibronectin receptor alpha 5 beta 1, the vitronectin receptor alpha v beta 5, and the collagen receptor alpha 2 beta 1 by differentially modulating the synthesis of their alpha and beta subunits; (b) downregulates the multifunctional alpha 3 beta 1 heterodimer; (c) induces the de novo expression and surface exposure of the alpha v beta 6 fibronectin receptor; (d) stimulates keratinocyte migration toward fibronectin and vitronectin; (e) induces a marked perturbation of the general mechanism of polarized domain sorting of both beta 1 and beta 4 dimers; and (f) causes a pericellular redistribution of alpha v beta 5. These data suggest that alpha 5 beta 1, alpha v beta 6, and alpha v beta 5, not routinely used by keratinocytes resting on an intact basement membrane, act as "emergency" receptors, and uncover at least one of the molecular mechanisms responsible for the peculiar integrin expression in healing human wounds. Indeed, TGF-beta 1 reproduces the integrin expression pattern of keratinocytes located at the injury site, particularly of cells in the migrating epithelial tongue at the leading edge of the wound. Since these keratinocytes are inhibited in their proliferative capacity, these data might account for the apparent paradox of a TGF-beta 1-dependent stimulation of epidermal wound healing associated with a growth inhibitory effect on epithelial cells.
Zambruno
G
G
Department of Dermatology, University of Modena, Italy.
Marchisio
P C
PC
Marconi
A
A
Vaschieri
C
C
Melchiori
A
A
Giannetti
A
A
De Luca
M
M
D016475:3T3 Cells; D000818:Animals; D000951:Antigens, Neoplasm; D015152:Blotting, Northern; D002465:Cell Movement; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D006801:Humans; D039641:Integrin beta Chains; D019012:Integrin beta1; D016023:Integrins / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D011233:Precipitin Tests; D012867:Skin / Q000166:cytology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014945:Wound Healing / Q000502:physiology
D000951:Antigens, Neoplasm; D039641:Integrin beta Chains; D019012:Integrin beta1; D016023:Integrins; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6; C084344:integrin beta5