542 Dysregulation of CCN proteins in Systemic Sclerosis patients with pigmentary disorders

Abstract

542 Dysregulation of CCN proteins in Systemic Sclerosis patients with pigmentary disorders P Henrot, C Pain, J Seneschal, A Taieb, M Truchetet and M Cario-Andre 1 University Bordeaux, Bordeaux, France and 2 Rheumathology unit, CHU Bordeaux, Bordeaux, France Pathogenesis of Systemic Sclerosis (SSc) is complex and includes impaired communication between endothelial cells, epithelial cells and fibroblasts, leading to inflammation and connective tissue fibrosis such as dermal fibrosis. About half of the patients present pigmentation patches. It is already known that CCN2 is increased in SSc and that polymorphism of its promoter is associated with the disease. CCN2 is part of a family of 6 members, including CCN3, which often antagonizes CCN2. In SSc, CCN2 upregulation is sustained by an autocrine activating loop of endothelin 1, a well-known pigmentary factor. We hypothesize that in patients with pigmentary disorders, secretion of CCN by dermal cells is dysregulated (isoforms, levels). Thus, we plan to study the expression profile of CCNs, among other factors implicated both in fibrosis and pigmentation in SSc patients presenting or not skin pigmentary disorders. Our preliminary data revealed that level of expression of CCN3 observed by immunohistochemistry or in fibroblasts protein extract differed in lesional and non-lesional areas. Moreover, SSc patients presented various CCN3 isoforms according to pigmentary status. CCN2 examination also revealed variation of its expression as compared to healthy controls. Interestingly, these abnormalities could also be found in apparently nonlesional skin areas from SSc patients, which suggests that CCN2 and 3 expression are altered at early stages of the disease. Differential level of expression and presence of various isoforms of CCNs have to be confirmed in fibroblasts and endothelial cells according to the pigmentary status of the fibrotic areas. This will allow us to verify our hypothesis of two different types of SSc, depending on time of apparition and localization of pigmentary patches. This could help to detect the disease early, which is essential for therapeutic issues. Moreover, if spatiotemporal variations of CCN are confirmed, it could allow to develop specific therapeutic window for the use of CCNs modulators. 543 UVA irradiation of senescence fibroblasts epigenetically unlock anti-apoptotic GDF15 expression via interleukin-6 mediated promoter demethylation in melanoma cells A Basu, V Farsam, K Singh, D Kletsas, B Schumacher, M Wlaschek and K Scharffetter-Kochanek 1 Dermatology and Allergic Diseases, Dermatology and Allergic Diseases, ULM, Germany, 2 Laboratory of Cell Proliferation & Ageing, Institute of Biosciences & Applications NCSR “Demokritos”, Athens, Greece and 3 Genome Stability in Ageing and Disease, CECAD Forschungszentrum, Koln, Germany The incident of cutaneous melanoma is rapidly increasing in many developed countries with augmentative numbers of aged patients with a galore of evidence exist that cutaneous malignant melanoma is cogitated with exposure to sunlight; most likely to its UV component including tanning beds. Although much investigation upon aging, it’s associated SASP and tumor progression has been carried in the recent years, still not much is known about UVA mediated gene alteration in elderly and its underlying mechanism contributed by senescence fibroblast. Over the past few years, strong evidence has accumulated that p53 engages also in transcriptionally regulating powerful pro-survival pathways by active transcription of genes associated with counteracting apoptosis. Among many p53 transcriptionally regulated genes, GDF15 coding for the Growth Differentiation Factor 15 (GDF15) protein most likely plays a role in regulating inflammatory and anti-apoptotic pathways in melanoma progression. However, the underlying molecular mechanisms regulating the balance between apoptosis and anti-apoptosis though p53 transcription factor is so far not fully understood. Here we report for the first time that anti-apoptotic gene GDF15 is epigenetically regulated by IL-6 upon induction with UVA. Under direct UVA exposure GDF15 is downregulated both in Senescence fibroblast and melanoma cells, but this also influences a strong UVA mediated paracrine secretion of IL-6 in senescence fibroblast, hypo-methylating GDF15 gene promoter and thereby through p53 mediated transcription leads to the release the epigenetic lock in UVA exposed melanoma cells which imparts pro-survival mechanism to melanoma progression.