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TGF-ß Receptor Types I and II Are Differentially Expressed during Corneal Epithelial Wound Repair

From the Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.

PURPOSE. It has been demonstrated that cells migrating to cover an epithelial débridement wound exit the cell cycle and that the cell-cycle inhibitor p15^INK4b is upregulated in these cells. TGF-ß signaling has been implicated in both of these processes, and this study was conducted to determine whether the expression and localization of TGF-ß receptor (TßR)-I and -II are altered during corneal epithelial wound repair.

METHODS. Three-millimeter superficial keratectomy wounds and 3-mm débridement wounds were made in central rat cornea and allowed to heal in vivo for 1 to 48 hours. Immunofluorescence microscopy and Western blot analysis were used to determine the localization and expression of TßR-I and -II. Unwounded rat corneas served as control samples. To determine the effect of epidermal growth factor (EGF) and TGF-ß1 on p15^INK4b and TßR-I and -II expression, human corneal epithelial cells were grown in culture to 50% to 60% confluence, and EGF (5 ng/ml) and/or TGF-ß1 (2 ng/ml) were added for 6 hours. Cells were harvested and p15^INK4b and TBR-I and -II levels were assayed by using Western blot analysis.

RESULTS. In unwounded corneas, TßR-I and TßR-II were present at low levels across the cornea, with higher levels in limbal epithelium. Both TßR-I and -II were upregulated after wounding. However, levels of TßR-II appeared to increase in the epithelial cells that had migrated to cover the wound area, whereas TßR-I was upregulated in the entire corneal epithelium. Western blot analysis indicated that both TßR-I and -II were upregulated threefold after wounding. In cultured cells, EGF and TGF-ß1 stimulated TßR-II; however, neither one stimulated TßR-I expression. TGF-ß1 stimulated p15^INK4b protein levels threefold.

CONCLUSIONS. After wounding, TßR-I and TßR-II were both expressed at high levels in cells migrating to cover a corneal wound, suggesting that TGF-ß signaling is involved in blocking migrating cells from progressing through the cell cycle. This blockage, at least in part, involves the inhibitor p15^INK4b. In addition, although both TßR-I and TßR-II are upregulated during wound repair, they appear to be differentially regulated.

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