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New Gold Compound Shows Immunesuppressive Functions and Leads to an Amelioration of Skin Inflammation

出版	2017
URL	http://books.google.com.hk/books?id=9OayzQEACAAJ&hl=&source=gbs_api

註釋The aryl hydrocarbon receptor (AHR) functions in various biological processes in a ligand-dependent manner. Upon ligand binding the receptor translocates into the nucleus and acts as a transcription factor. We could show that a newly generated gold metal compound 3 (MC3) binds to the aryl hydrocarbon receptor (AHR). Binding was 100-fold stronger compared to the AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). To investigate the in vitro immunosuppressive function of MC3, primary murine WT CD4+ T cells were isolated and treated over night with MC3 followed by stimulation with CD3/CD28. Treatment with MC3 showed an upregulation of CYP1A1 and TGFu03b21, TGFu03b22 and TGFu03b23 in comparison to mock solution using real time PCR. In addition, flow cytometry analysis showed a 2-3 fold higher CD4+CD25+foxP3+Treg frequency upon MC3 treatment in comparison to mock treated CD4+ T cells. Furthermore, the increased Treg frequency could be reversed by using AHR antagonists or TGFu00df inhibitors in vitro. The effect of MC3 was additionally investigated using an autoimmune-mouse model. Scurfy mice lack functional Treg and show activation of autoreactive T cells which leads to T-cell mediated inflammation of several organs including liver, lung and skin. On average scurfy mice die due to multi-organ failure at day 24 of life. When treated with MC3, scurfy mice showed a prolonged life expectancy up to 70 days. Furthermore, we found after 24 days treatment a reduction in the frequencies of activation markers (CD69, CD25) on CD4+ pre-gated T cells in comparison to mock-treated mice. RtPCR data show that MC3 treated mice (WT and scurfy) have higher TGFu03b21 expression in liver, spleen and thymus in comparison to mock treated mice. Similar results could be shown by TGFu03b21 in-situ staining of thymus and liver.In summary, the new gold compound MC3 functions as AHR agonist which induces increased TGFu03b21 expression and thereby might lead to Treg induction. Furthermore MC3 has an immunosuppressive effect on T cells in an autoimmune model and increases the life expectancy of scurfy mice.