American Society for Photobiology

ASP Conference 2016: 21-26 May 2016
Tampa Marriott Waterside Hotel & Marina


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20 - Frontiers in the Mechanisms of UV-induced Inflammation

Florida 2   10:00 - 12:00

Chair(s): Shiyong Wu
 
20-1   08:00  New Evidence for an Essential Role of the p38/MSK1/NFkappaBp65Ser276 Axis during Intracellular Signaling Pathways Leading to UVB-induced Cutaneous Inflammation and Hyperkeratinization G Imokawa*, Chubu University ; S Terazawa, Chubu University; S Mori, Tokyo University of Technology; M Yasuda, Tokyo University of Technology; H Nakajima, Tokyo University of Technology

Abstract: UVB exposure is the most harmful stimulus that deteriorates healthy skin. These effects mainly include cutaneous inflammation and abnormal keratinization where prostaglandin E2, cyclooxygenase (COX)2, macrophage granulocyte colony stimulatory factor (GM-CSF), interleukin (IL)-8 and transglutaminase 1 (TGase1), play pivotal roles. The stimulated expression of those factors has been implicated to be highly associated with the signaling axis leading to the facilitated translocation of NFkB from the cytosol to nuclei during UVB-activated signaling cascades. However, the possible therapeutic interruption of those signaling cascades has a definite risk because inhibiting many of the signaling factors, such as p38, ERK and JNK is required for complete interruption but may also abolish constitutive anti-UVB carcinogenetic cascades, such as apoptotic signaling. Fortunately, we have discovered an interesting phenomenon where the specific inhibition of only mitogen-stress activated protein kinase (MSK)-1, is attainable by astaxanthin (AX) or by MSK1 inhibitor H89 and results in a remarkable abrogation of the increased expression of those inflammatory and keratinization factors. We found that post-irradiation treatment with AX or H89 significantly abrogates the increased expression of COX2, PGE2, GM-CSF, IL-8 and TGase1, which is accompanied by a specific abrogation of the phosphorylation of MSK1 and NFkappaBp65Ser276 without any suppressive effects on the activation of p38, ERK, JNK and casein kinase or on the stimulated translocation of NFkB from the cytosol to nuclei in UVB-exposed human keratinocytes. We have also confirmed an association between the specific inhibition of MSK1 activation and the attenuated expression of TGase1 by silencing MSK1 in UVB-exposed human keratinocytes. This suggests an essential role of the p38/MSK1/NFkappaBp65Ser276 axis during intracellular signaling pathways leading to UVB-induced cutaneous inflammation and hyperkeratinization.

20-2   08:20  Regulation of cutaneous inflammation by Thrombospondin-1 X Tong, Northwestern University, Chicago, IL, USA ; S Mirzoeva, Northwestern University, Chicago, IL, USA; B Bridgeman, Northwestern University, Chicago, IL, USA; MP Plebanek, Northwestern University, Chicago, IL, USA; M Cornwell, North Shore University Research Group, Evanston, IL, USA; SE Crawford, North Shore University Research Group, Evanston, IL, USA; OV Volpert*, Northwestern University, Chicago, IL, USA

Abstract: Ultraviolet B (UBV) radiation is the main cause of non-melanoma skin cancer, whose incidence steadily increases despite the use of sunblock agents. Thus new agents and mechanisms useful for prevention or treatment of UVB-induced cancer are highly important. The contribution of UVB-induced inflammation and immunosuppression, respectively, are critical for UVB-induced skin carcinogenesis. While critical roles of endogenous angiogenesis inhibitor thrombospondin-1 (TSP1) in cutaneous angiostasis is well established its immunomodulatory effects in UVB-irradiated skin are not well understood. Importantly, TSP1 expression is potently inhibited by UVB. Using TSP-1 null hairless mice we have demonstrated that the lack of endogenous TSP1 causes dramatic increases in UVB-induced cutaneous angiogenesis and acute inflammation as well as baseline inflammatory activity. Seeking immune cell populations affected TSP1 we found profound differences between the myeloid cell populations in the bone marrow of the wild type and TSP-1 null mice exposed to UVB radiation and the recruitment of the circulating myeloid cells. These differences translated in significantly increased macrophage infiltration and neutrophil presence in the UVB-exposed skin. In addition, the lack of endogenous TSP1 strongly altered cytokine profile in skin keratinocytes and in circulation in a way that favored inflammatory and proliferative activities. Importantly, restoring TSP1 function in UVB-irradiated skin and in TSP1-null mice with small bioactive peptide mimetics significantly decreased UVB-induced skin edema, inflammatory infiltrates and cytokine production. Our analyses point to the critical role of TSP1 in cutaneous inflammation and potential utility of TSP1 peptide mimetic to mitigate the UVB inflammatory effects in skin.

20-3   08:40  UV-induced inflammation at the molecular, cellular, and organismal levels Yu-Ying He*, University of Chicago

Abstract: Skin cancer is the most common cancer in the US. The incidence of skin cancer continues to rise at an alarming rate annually. Exposure to ultraviolet B radiation (UVB, 280-315 nm) from the sun is the major environmental risk factor for skin cancer. UV radiation causes DNA damage and lead to accumulation of oncogenic mutations. In addition, UV also damages self noncoding RNA to mediate acute the inflammatory response, collectively known as sunburn. In humans, sunburn sensitivity is positively associated with increased risk of skin cancer including both non-melanoma skin cancer and melanoma. However, the mechanism in regulating UV-induced inflammation is not well understood. Here we show the molecular basis for regulation of UV-induced inflammation at the molecular, cellular, and organismal levels.

20-4   09:00  Carnosol as a therapeutic compound in preventing and treating UVB-induced skin cancer through its anti-inflammatory and pro-apoptosis characteristics. L Tong*, Ohio University ; S Wu, Ohio University

Abstract: Repeated overexposure of ultraviolet B (UVB) radiation is known to be carcinogenic, although the detailed mechanisms remain ambiguous. Carnosol is a natural compound extracted mainly from rosemary and sage leaves, which is edible and thus environmental friendly. It has been shown to have anti-inflammatory and anti-cancer effects. However, very little is known on the effect of carnosol on UVB-induced skin cancer. In this report, we studied the effect of carnosol on UVB-induced non-melanoma skin cancer formation and progression. By repeated exposing to UVB radiation, normal human skin cells can be transformed to cancerous skin cells, while treating the cells with carnosol could significantly reduce the transformation rate. The mechanisms possibly relies on the fact that carnosol can partially reduce UVB-induced reactive oxygen species (ROS) elevation and thus protect UV-induced DNA damage in normal skin cells. Our data also demonstrated that carnosol can impede the UVB-induced NF-kappaB activation, by protecting IkappaB degradation and thus reduce NF-kappaB phosphorylation level at active site and reduces its DNA binding activity. The manipulation of NF-kappaB activity in turn affects a series of cellular responses including inflammation and cell survival signaling pathways. In addition, carnosol can also prohibit skin cancer cell progression with or without UV radiation. Based on our data, carnosol could be a potential therapeutic for chemoprevention and treatment of UVB-induced skin cancers.

20-5   09:20  Antioxidant baicalin displays a higher toxic impact on p53-mutated keratinocytes (HaCat or A431 carcinoma cells) versus normal human keratinocytes. F Boissout, L'Oreal R&I ; P Perez, L'Oreal R&I; J Soeur, L'Oreal R&I; L Marrot*, L'Oreal R&I

Abstract: Baicalin is a flavonoid present in Scutellaria baicalensis and its anti-inflammatory and antioxidant properties have been well described. Moreover, anti-tumorigenic activity of baicalin has also been reported in leukemia or pancreatic cancer. In the dermatological field, some studies have shown that baicalin could protect skin against UV stress, but data dealing with skin cancer targeting are scarce. In this study, biological effects of baicalin were investigated on precancerous HaCaT keratinocytes and on human skin carcinoma cell line A431 (both cell types harboring UV-induced p53 mutations) compared to primary normal keratinocytes (NHEK). In a defined range of concentrations (between 0.1 and 1 mM) baicalin selectively killed HaCaT and A431 whereas it displayed almost no toxic effect on NHEK. To mimic the situation of patches involving p53-mutated cells often found in photo-aged skin, a co-culture model (HaCaT + NHEK) was used. This approach further demonstrated the preferential toxicity of baicalin towards HaCaT. Investigation of mechanisms involved in baicalin-induced cell death was performed comparing monoculture HaCaT versus NHEK. We observed that apoptosis was the main pathway as shown by flow cytometry using annexin-V labelling and caspase activity on a fluorescent peptide. These results suggest that baicalin could reduce clonogenic expansion of p-53 mutated epidermal cells in addition to providing an anti-oxidant protection. Such a flavonoid, and also natural extracts containing baicalin, might be interesting compounds in skin photocancer prevention.



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