THE REGULATORY MECHANISM OF HAEM OXYGENASE PROTECTION AGAINST PHOTOIMMUNOSUPPRESSION AND SKIN CANCER

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Current dogma holds that UVA radiation adds to UVB damage in the skin. However we have identified a window of UVA doses, easily achievable from daytime sunlight exposure, that do not cause sunburn and are not immunosuppressive, but that significantly attenuate the damaging effects of UVB. In mice the mechanism partially depends on the UVA-upregulated cytokine interferon-gamma, and strongly on the UVA-inducible antioxidant enzyme haem oxygenase-1 (HO-1). This project aims to establish how the HO-1 gene is regulated by UVA. Available data from cultured human skin cells suggest that HO-1 is UVA-inducible in fibroblasts but not keratinocytes, whereas we found both cell types respond in mouse skin, keratinocytes most actively. We will ascertain whether a species difference, or an anomaly in cultured cells, underlies these discrepancies. With human skin grafted onto immunodeficient SCID mice, we will study impaired immune function, an important prerequisite for cancer, compared with mouse skin in vivo. Using molecular biology techniques with this model, we will monitor the activity of the transcription factor Bach 1, known to bind to the DNA of the HO-1 promoter region to repress the gene normally, but reversibly by haem-binding, and the corresponding activity of HO-1, during immunoprotective (UVA exposure, haem elevated) conditions. Immunoprotection may result from binding by Bach 1 of haem released from microsomal proteins by UVA, its release from DNA and thus derepression of HO-1. We will seek evidence of a role for skin cytokines in modifying Bach 1 binding, and for Bach 1 and HO-1 actions during photocarcinogenesis induction with chronic UV exposure. The significance of the outcome of the studies will be in understanding how a natural ameliorating pathway induced by UVA radiation could be utilised for superior photoprotection strategies for skin cancer susceptible humans.