Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells.
Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells.
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DOI：
10.1084/jem.20100977
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发表时间：
2011-10-24
期刊：
影响因子：
--
通讯作者：
Röcken M
中科院分区：
文献类型：
--
作者：
Ghoreschi K;Brück J;Kellerer C;Deng C;Peng H;Rothfuss O;Hussain RZ;Gocke AR;Respa A;Glocova I;Valtcheva N;Alexander E;Feil S;Feil R;Schulze-Osthoff K;Rupec RA;Lovett-Racke AE;Dringen R;Racke MK;Röcken M
富马酸盐通过阻断树突状细胞通过不同途径产生IL-12和IL-23来抑制Th 1应答。富马酸盐改善多发性硬化症（MS）和银屑病，这两种疾病中IL-12和IL-23均促进致病性T辅助（Th）细胞分化。然而，这两种疾病对大多数既定疗法表现出相反的反应。首先，我们在人体中表明，富马酸盐治疗在体内诱导产生IL-4的Th 2细胞，并产生产生IL-10而不是IL-12和IL-23的II型树突状细胞（DC）。在小鼠中，谷氨酸盐还产生II型DC，其在体外和体内诱导产生IL-4的Th 2细胞，并保护小鼠免受实验性自身免疫性脑脊髓炎。II型DCs是由于叶酸诱导的谷胱甘肽（GSH）耗竭，随后是血红素加氧酶-1（HO-1）表达增加和STAT 1磷酸化受损所致。诱导的HO-1被切割，于是HO-1的N-末端片段易位到细胞核中并与IL-23 p19启动子的AP-1和NF-κB位点相互作用。这种相互作用阻止IL-23 p19转录而不影响IL-12 p35，而STAT 1失活阻止IL-12 p35转录而不影响IL-23 p19。因此，GSH消耗的小分子，如谷氨酸诱导小鼠和人类的II型树突状细胞，改善炎症性自身免疫性疾病。这种治疗方法通过干扰IL-12和IL-23的产生来改善Th 1和Th 17介导的自身免疫性疾病，如银屑病和MS。
Fumarates suppress Th1 responses by blocking IL-12 and IL-23 production by dendritic cells via distinct pathways. Fumarates improve multiple sclerosis (MS) and psoriasis, two diseases in which both IL-12 and IL-23 promote pathogenic T helper (Th) cell differentiation. However, both diseases show opposing responses to most established therapies. First, we show in humans that fumarate treatment induces IL-4–producing Th2 cells in vivo and generates type II dendritic cells (DCs) that produce IL-10 instead of IL-12 and IL-23. In mice, fumarates also generate type II DCs that induce IL-4–producing Th2 cells in vitro and in vivo and protect mice from experimental autoimmune encephalomyelitis. Type II DCs result from fumarate-induced glutathione (GSH) depletion, followed by increased hemoxygenase-1 (HO-1) expression and impaired STAT1 phosphorylation. Induced HO-1 is cleaved, whereupon the N-terminal fragment of HO-1 translocates into the nucleus and interacts with AP-1 and NF-κB sites of the IL-23p19 promoter. This interaction prevents IL-23p19 transcription without affecting IL-12p35, whereas STAT1 inactivation prevents IL-12p35 transcription without affecting IL-23p19. As a consequence, GSH depletion by small molecules such as fumarates induces type II DCs in mice and in humans that ameliorate inflammatory autoimmune diseases. This therapeutic approach improves Th1- and Th17-mediated autoimmune diseases such as psoriasis and MS by interfering with IL-12 and IL-23 production.
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T-BET的丧失，但不是STAT1阻止了实验性自身免疫性脑脊髓炎的发展。
影响因子：
15.3
作者：
Bettelli, E;Sullivan, B;Szabo, SJ;Sobel, RA;Glimcher, H;Kuchroo, VK
通讯作者：
Kuchroo, VK
I型Interferon自分泌 - 核酸环与树突状细胞的Toll样受体诱导的白介素-12p70分泌有关。
影响因子：
15.3
作者：
Gautier, G;Humbert, M;Deauvieau, F;Scuiller, M;Hiscott, J;Bates, EEM;Trinchieri, G;Caux, C;Garrone, P
通讯作者：
Garrone, P
影响因子：
82.9
作者：
Ghoreschi, K;Thomas, P;Röcken, M
通讯作者：
Röcken, M
影响因子：
168.9
作者：
Kappos, Ludwig;Gold, Ralf;O'Neill, Gilmore N.
通讯作者：
O'Neill, Gilmore N.
影响因子：
5.5
作者：
Ghashghaeinia, Mehrdad;Bobbala, Diwakar;Ghoreschi, Kamran
通讯作者：
Ghoreschi, Kamran