INVOLVEMENT OF TRANSFORMING GROWTH-FACTOR-ALPHA AND ITS RECEPTOR IN THE GROWTH-RESPONSE OF CULTURED HUMAN EPIDERMAL-CELLS TO RETINOIC ACID

Topical application of all-trans-retinoic acid (RA) to normal or photo damaged human skin causes pronounced growth effects on the epidermis ( hyperplasia) by mechanisms poorly understood. This paper describes inv estigations concerning the possible involvement of transforming growth factor-alpha (TGFalpha) and its receptor in the growth stimulatory re sponse of cultured human epidermal cells to RA. In a defined medium co ntaining epidermal growth factor (EGF), RA (0.1-1.0 muM) was found to increase epidermal cell number and size as determined by uptake of neu tral red dye. The stimulatory effect of RA was inhibited by a blocking monoclonal antibody directed against the binding domain of the EGF re ceptor. Relative to conditioned medium from cells grown in the absence of RA, conditioned medium from epidermal cells treated with RA contai ned increased concentrations of functionally active TGFalpha as determ ined by radioimmunoassays and radioreceptor assays. In addition, we fo und a marked reduction in the ability of TGFalpha to bind epidermal ce lls treated with RA. Decreased TGFalpha binding capacity is thought to be due to the ability of RA to stimulate TGFalpha, thereby resulting in EGF receptor binding and internalization. These results lead us to speculate that RA is capable of stimulating the secretion of TGFalpha by epidermal cells in vivo. TGFalpha may then act in an autocrine mann er to mediate the hyperplastic response of the epidermis to topical RA treatment.