The approximately 1.3 million new cases of nonmelanoma skin cancers diagnosed each year in the USA have a tremendous impact on public health and healthcare expenditures. Therefore, safe and effective chemopreventive strategies are urgently needed. Overexposure to solar ultraviolet (UV) radiation is a primary risk factor and that UV-induced immunosuppression plays a critical role in skin carcinogenesis. It is well established that UV irradiation induces inflammatory mediators, impairs the function of dendritic cells (DC) and effector T cells and induces suppressor T cells. UV-induced epigenetic modifications, such as DNA hypermethylation, seem to play an important role in photodamage of the skin. A model is now emerging that suggests that epigenetic modifications, including DNA hypermethylation, are induced by UVB-induced inflammatory mediators, such as cyclooxygenase-2 (COX-2)/prostaglandin E2, and act as a mechanistic link between the inflammatory mediators and compromised DC function. We have demonstrated that topical administration of honokiol, a phytochemical from the Magnolia plant, prevents both photocarcinogenesis and UVB-induced immunosuppression in mice. Our preliminary data further indicate that honokiol can correct or inhibit DNA hypermethylation in UV-exposed dendritic cells and that this restores dendritic cell-mediated activities including stimulation of cells. We propose to test the innovative hypothesis that inhibition of UVB-induced DNA hypermethylation by honokiol is critical for its chemopreventive effects on UV- induced immunosuppression. We propose three inter-related Specific Aims to test the hypothesis in a mouse model: (1) Determine whether honokiol-induced inhibition of UV-induced immunosuppression occurs through DNA demethylation in UV-exposed skin and whether the inflammatory mediators play a role in this; (2) Determine whether honokiol inhibits the development of UV-induced tolerogenic DCs and whether this is mediated through inhibition of DNA hypermethylation; and (3) Determine whether honokiol inhibition of UV- induced immunosuppression occurs through enhancement of T cell activation and whether this is mediated through inhibition of DNA hypermethylation. A combination of approaches will be utilized to verify the results including the use of COX-2 deficient mice. Innovation: The proposed studies will: (1) Identify the mechanisms by which topical or oral administration of honokiol acts to correct UV-induced immunosuppression and prevent photocarcinogenesis, thereby providing data needed for further clinical development of this promising phytochemical; and (2) The data generated will provide critical insights into the mechanisms that elicit UVB- induced DNA hypermethylation in DC and establish whether targeting of these mechanisms is sufficient to prevent UVB-induced immunosuppression. Impact: The development of new early intervention strategies using honokiol may help to reduce the risk of skin cancer in humans, as the risk of skin cancer is a major public health concern.
In this application we will determine the chemopreventive mechanism of honokiol, a phytochemical from Magnolia plant, on UVB-induced immunosuppression, as UVB-induced immunosuppression has been implicated in the risk of nonmelanoma skin cancers. This study will identify whether blocking of inflammation and subsequently DNA hypermethylation by honokiol is critical for its chemopreventive effects on UV-induced immunosuppression and photocarcinogenesis. The generation of new knowledge will provide novel insights into the mechanisms by which honokiol can either correct, or compensate for, the UV-induced photodamage that triggers or promotes photocarcinogenesis.
|Prasad, Ram; Katiyar, Santosh K (2016) Crosstalk Among UV-Induced Inflammatory Mediators, DNA Damage and Epigenetic Regulators Facilitates Suppression of the Immune System. Photochem Photobiol :|