DISSOCIATION OF ERYTHEMA AND P53 PROTEIN EXPRESSION IN HUMAN SKIN FOLLOWING UVB IRRADIATION, AND INDUCTION OF P53 PROTEIN AND MESSENGER-RNAFOLLOWING APPLICATION OF SKIN IRRITANTS

The mechanisms mediating the varied effects of ultraviolet radiation ( UVR) on human skin are unclear, although a relationship between erythe ma and DNA damage is suggested by photosensitivity in xeroderma pigmen tosum. Increased p53 expression in response to UVR is thought to refle ct direct DNA damage, but recent evidence indicates that UVR also acti vates membrane and cytosolic signal transduction pathways. In this stu dy, we have investigated the relationship between erythema and p53 ind uction following UVB and whether this p53 response is specific to UVR. p53 protein expression was determined by immunocytochemistry using th e monoclonal antibody DO7, and p53 mRNA expression was examined by non -isotopic in situ hybridization. Incremental doses of UVB were adminis tered to the lower back of eight subjects. Immunostaining revealed tha t p53 positive nuclei were significantly increased 8 h after suberythe mogenic doses of UVB (79 +/- 12), compared to normal unirradiated skin (8 +/- 6, p < 0.0005), but no change in p53 mRNA was seen. Higher UVB doses, which resulted in moderate erythema, resulted in a similar or greater induction of p53 protein. Indomethacin (1% w/v), applied immed iately after UVB irradiation, significantly inhibited UVB erythema at 8 h in six subjects (p < 0.005), but did not reduce p53 immunostaining . Dithranol (1 mu g/mu 1, n = 8), sodium dodecylsulphate (5%, n = 4), and retinoic acid (0.5%, n = 4), applied for 48 h, caused erythema, si gnificantly increased p53 protein levels (p < 0.05), and also increase d p53 mRNA. Our results show that in human skin, UVB-induced p53 eleva tion can be dissociated from erythema and skin irritants can also indu ce p53 protein. The induction of p53 mRNA by irritants but not UVR sug gests different mechanisms of action.