TRANSFORMING GROWTH FACTOR-BETA(1) INDUCTION IS ASSOCIATED WITH TRANSFORMING GROWTH FACTOR-BETA(2) AND FACTOR-BETA(3) DOWN-MODULATION IN 12-O-TETRADECANOYLPHORBOL-13-ACETATE-INDUCED SKIN HYPERPLASIA

Acute treatment of mouse skin with the tumor promoter 12-O-tetra-decan oylphorbol-13-acetate (TPA) induces marked epidermal hyperplasia, whic h is well evident by 24 h and maximal by 48-72 h. These effects are as sociated with the early induction of transforming growth factor (TGF) beta1 expression in the epidermis. We show here that, in contrast to T GF-beta1, TGF-beta2, and TGF-beta3, skin expression is significantly d own-modulated in response to TPA. TGF-beta3 RNA levels decreased by 6 h of treatment but returned to normal or even higher levels at later t imes. The TGF-beta3 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-beta3 was found only in dermal cells and not in the epidermis. TGF-beta2 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 homeostasi s and could be at least partially responsible for TPA-induced skin hyp erplasia.