TGF-beta 3, but not TGF-beta 1, protects keratinocytes against 12-O-tetradecanoylphorbol-13-acetate-induced cell death in vitro and in vivo

We have examined the role that individual TGF-beta isoforms, and in particu lar TGF-beta 3, play in control of epidermal homeostasis, Mice with a knock out mutation of the TGF-beta 3 gene die a few hours after birth. A full-thi ckness skin grafting approach was used to investigate the postnatal develop ment and homeostatic control of the skin of these mice. Grafted skin of mic e with a disruption of the TGF-beta 3 gene developed similarly to grafts of wild type and TGF-beta 1 knockout animals. However, a strikingly different response was observed after acute treatment with the tumor promoter 12-O-t etradecanoylphorbol-13-acetate (TPA), When exposed to TPA, the grafted skin of wild type and TGF-beta 1 knockout mice underwent a hyperplastic respons e similar to that of normal mouse skin. In marked contrast, TPA treatment o f TGF-beta 3 knockout grafts induced widespread areas of keratinocyte cell death. Analysis of cultured keratinocytes treated with purified TGF-beta is oforms revealed that TGF-beta 3 plays a direct and specific function in pro tecting keratinocytes against TPA-induced cell death. The protective functi on of TGF-beta 3 on TPA-induced cell death was not because of general suppr ession of the signaling pathways triggered by this agent, as ERK1/2 activat ion occurred to a similar if not greater extent in TGF-beta 3-treated versu s control keratinocytes. Instead, TGF-beta 3 treatment led to a significant reduction in TPA-induced c-Jun N-terminal kinase activity, which was assoc iated and possibly explained by specific counteracting effects of TGF-beta 3 on TPA-induced disruption of keratinocyte focal adhesions.