TGF-β3, but not TGF-β1, 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 particular TGF-beta 3, play in control of epidermal homeostasis, Mice with a knockout mutation of the TGF-beta 3 gene die a few hours after birth. A full-thickness skin grafting approach was used to investigate the postnatal development and homeostatic control of the skin of these mice. Grafted skin of mice 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-tetradecanoylphorbol-13-acetate (TPA), When exposed to TPA, the grafted skin of wild type and TGF-beta 1 knockout mice underwent a hyperplastic response similar to that of normal mouse skin. In marked contrast, TPA treatment of TGF-beta 3 knockout grafts induced widespread areas of keratinocyte cell death. Analysis of cultured keratinocytes treated with purified TGF-beta isoforms revealed that TGF-beta 3 plays a direct and specific function in protecting keratinocytes against TPA-induced cell death. The protective function of TGF-beta 3 on TPA-induced cell death was not because of general suppression of the signaling pathways triggered by this agent, as ERK1/2 activation occurred to a similar if not greater extent in TGF-beta 3-treated versus control keratinocytes. Instead, TGF-beta 3 treatment led to a significant reduction in TPA-induced c-Jun N-terminal kinase activity, which was associated and possibly explained by specific counteracting effects of TGF-beta 3 on TPA-induced disruption of keratinocyte focal adhesions.