Human epidermal cells produce a wide range of cytokines, including those characteristic of Th2-like responses such as interleukin (IL)-4 and IL-10. As well, keratinocytes have recently been shown to produce Th1-like cytokines such as IL-12. Exposure to UVB has profound effects on the skin and systemic immune system, which is in part mediated by secretion of tumor necrosis factor (TNF)-alpha by epidermal cells. Because IL-12 induces production of TNF-alpha by certain cells of the immune system, we sought to determine whether UVB is an inducer of IL-12 gene expression in epidermal cells. Human epidermal cells were exposed to UVB radiation in vivo, isolated by suction blister technique and trypsinization and transcription of the IL-12 p35 and p40 chains was examined by RT-PCR. We found the p35 chain of IL-12 to be constitutively expressed and the p40 chain inducible by UVB irradiation. Because epidermis consists of a heterogenous cell population with distinct cytokine repertoires, we sought to determine the cellular source of the IL-12 message after UVB exposure. After depleting UVB-exposed epidermal cells for DR+ cells, no reduction in the IL-12 activity was detected, suggesting that keratinocytes are a source of IL-12 transcripts in UVB-exposed human epidermis. This was supported by the up-regulation of IL-12 p40 transcripts in UV-irradiated cultured keratinocytes that were devoid of DR+ cells. Up-regulation of IL-12 p40 gene expression by UVB as demonstrated here, taken together with the finding that keratinocytes also up-regulate IL-10 transcription, suggests that there is a complex interplay between Th1- and Th2-like epidermis-derived cytokines following exposure to UVB.