342 Differential induction of ATF3 and HO-1 in myeloid cells and keratinocytes via Dimethylfumarate or Cyclosporine A

Abstract

Important inflammatory skin diseases such as psoriasis, lichen planus or atopic dermatitis are characterized by a hyperplasia of the epidermis. In these diseases, proliferation is controlled and only rarely leads to cancer development which can be supported by an inflammatory microenvironment. One key factor which controls and regulates proliferation is the activating transcription factor 3 (ATF3). ATF3 is a dual function protein as it suppresses pro-inflammatory IL-6 and IL-8, but also acts as a pro-oncogenic factor by the suppression of p53. To dissect the bi-modal role of ATF3 we pharmacologically induced ATF3 and analyzed its influence on cytokine expression and secretion in a cell type specific manner comparing myeloid cells with keratinocytes. Since inflammatory skin diseases can be treated systemically with Cyclosporin A (CsA) or Dimethylfumarate (DMF), but only CsA treatment increases the risk of non-melanoma skin cancer, we used those drugs for the induction of ATF3. In the present study, we showed that ATF3 is induced in PBMCs by DMF, while CsA is the most prominent inducer of ATF3 in keratinocytes without enhancing HO-1 transcription. Further we could show that LPS treatment elevates IL-1β and IL-6 and weakly ATF3 transcription in PBMCs. While transcription of both cytokines is elevated, LPS treatment mediates IL-6 secretion with only little IL-1β secretion. Treatment with DMF dampens LPS-induced transcription. Taken together, our results shed light into the different carcinogenic potential of CsA and DMF, which both target ATF3. Collectively our data demonstrate that CsA strongly induces pro-carcinogenic ATF3 in keratinocytes, whereas ATF3 induction by DMF in myeloid cells acts anti-inflammatory.