(Verbatim) In addition to being a complete carcinogen, UV exposure is immune suppressive. Experiments with animals and studies with biopsy proven skin cancer patients have indicated that the immune suppression induced by UV exposure is a major risk factor for skin cancer induction. Because of the association between the carcinogenic and immune suppressive effects of UV radiation, it is critically important to determine the mechanisms involved in the induction of immune suppression. The hypothesis tested states that the release of immunomodulatory cytokines in response to UV exposure is responsible for inducing systemic immune suppression. During the initial funding period evidence was provided supporting this hypothesis. Following UV exposure, a cytokine cascade, including prostaglandin E2 (PGE2) interleukin (IL)-4 and IL-l0 is activated. The production of PGE2 is key in that a selective cyclooxygenase-2 inhibitor blocks both the production of serum IL-4 and 10 and abrogates UV-induced immune suppression. Moreover, evidence was generated to show that one consequence of UV irradiation is an alteration of dendritic cell production of IL-12. Rather than secreting biologically active ILl2p70, UV exposure induces the release of the immune suppressive IL-l2p40 homodimer. The focus of the present proposal is to elucidate the mechanisms involved in the production and suppressive activity of UV-induced cytokines.
The Specific Aims of the present proposal are: 1) Determine the mechanism(s) by which cytokines are induced in the skin following UV exposure. Are UV-responsive elements in the promoter region of the cyclooxygenase gene directly affected by UV radiation or are co-factors, such as histamine required? 2) What is the cellular source of the UV-induced serum IL-4? Is cytokine secretion by circulating T cells, mast cells and/or NK1. I cells involved in transmitting the suppressive signal from the skin to immune elements? 3) Is the inability of dendritic cells from UV-irradiated mice to active Th 1 cells due to secretion of the IL- l2p4O homodimer, a receptor antagonist reported to block activation of T helper (Th) I cells, while allowing Th2 cell activation? Is UV-induced PGE2, or IL-4 or IL-l0 involved in the production of the IL-12p40 homodimer? The long term goal of this research is to determine the mechanisms involved in the induction of immune suppression following UV exposure, concentrating on the role of cytokines. A better understanding of the mechanisms involved may help with the design of rational approaches to block the induction of immune suppression, thereby reducing one of the major risk factors for skin cancer induction.
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