Acute treatment of mouse skin with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) induces marked epidermal hyperplasia, which is well evident by 24 h and maximal by 48-72 h. These effects are associated with the early induction of transforming growth factor (TGF) beta 1 expression in the epidermis. We show here that, in contrast to TGF-beta 1, TGF-beta 2, and TGF-beta 3, skin expression is significantly down-modulated in response to TPA. TGF-beta 3 RNA levels decreased by 6 h of treatment but returned to normal or even higher levels at later times. The TGF-beta 3 protein could be detected immunohistochemically in both dermis and epidermis in control skins and at early times of TPA treatment. However, at later times, TGF-beta 3 was found only in dermal cells and not in the epidermis. TGF-beta 2 RNA expression was found to be significantly down-modulated by 24 h of TPA treatment and remained low even at later times. Thus, differential control of the 3 TGF-beta isoforms appears to be a likely determinant of normal skin homeostasis and could be at least partially responsible for TPA-induced skin hyperplasia.