Therapeutic effects of DZ2002, a reversible SAHH inhibitor, on lupus-prone NZBxNZW F1 mice via interference with TLR-mediated APC response
Therapeutic effects of DZ2002, a reversible SAHH inhibitor, on lupus-prone NZBxNZW F1 mice via interference with TLR-mediated APC response
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DZ2002（一种可逆 SAHH 抑制剂）通过干扰 TLR 介导的 APC 反应对易患狼疮的 NZBxNZW F1 小鼠产生治疗作用
DOI：
10.1038/aps.2013.167
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发表时间：
2014-02-01
影响因子：
8.2
通讯作者：
Zuo, Jian-ping
中科院分区：
文献类型：
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作者：
He, Shi-jun;Lin, Ze-min;Zuo, Jian-ping
目的：目的：探讨S-腺苷-L-同型半胱氨酸水解酶（SAHH）抑制剂DZ 2002对狼疮性NZB/WF 1小鼠的治疗作用及其机制mg.kg。处死小鼠后测定血清生化指标和肾损害。分离NZB/W F1小鼠的脾细胞用于离体研究。Toll样受体（TLR）刺激的人外周血单个核细胞（PBMC）或小鼠骨髓来源的树突状细胞（BMDCs）用于体外研究。这种改善伴随着致肾炎抗dsDNA IgG 2a和IgG 3抗体、血清IL-17、IL-23 p19和TGF-β水平的降低。在离体研究中，用DZ 2002治疗小鼠抑制了致病性Th 17细胞的发育，显著降低了IL-17、TGF-β、IL-6和IL-23 p19的产生，并阻碍了脾细胞中STAT 3蛋白和JNK/NF-κ B信号传导的活化。DZ 2002（500 μ mol/L）在体外显著抑制TLR激动剂刺激的人PBMC中树突状细胞IL-6、IL-12 p40、TNF-α、IgG和IgM分泌以及HLA-DR和CD 40表达的上调。DZ2002（100 μ mol/L）还显著抑制TLR激动剂刺激的小鼠BMDCs中IL-6和IL-23 p19产生的上调，并阻止BMDC-T细胞共培养系统中T细胞的Th 17分化和抑制IL-17分泌。DZ 2002通过调节TLR信号介导的抗原呈递细胞（APC）反应有效地改善NZB/W F1小鼠的狼疮综合征。
Aim: To examine the therapeutic effects and underlying mechanisms of DZ2002, a reversible S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor, on lupus-prone female NZBxNZW F1 (NZB/W F1) mice.Methods: Female NZB/W F1 mice were treated orally with DZ2002 (0.5 mg.kg(-1).d(-1)) for 11 weeks, and the proteinuria level and body weight were monitored. After the mice ware euthanized, serum biochemical parameters and renal damage were determined. Splenocytes of NZB/W F1 mice were isolated for ex vivo study. Toll-like receptor (TLR)-stimulated human peripheral blood mononuclear cells (PBMCs) or murine bone marrow-derived dendritic cells (BMDCs) were used for in vitro study.Results: Treatment of the mice with DZ2002 significantly attenuated the progression of glomerulonephritis and improved the overall health. The improvement was accompanied by decreased levels of nephritogenic anti-dsDNA IgG2a and IgG3 antibodies, serum IL-17, IL-23p19 and TGF-beta. In ex vivo studies, treatment of the mice with DZ2002 suppressed the development of pathogenic Th17 cells, significantly decreased IL-17, TGF-beta, IL-6, and IL-23p19 production and impeded activation of the STAT3 protein and JNK/NF-kappa B signaling in splenocytes. DZ2002 (500 mu mol/L) significantly suppressed TLR agonists-stimulated up-regulation in IL-6, IL-12p40, TNF-alpha, and IgG and IgM secretion as well as in HLA-DR and CD40 expression of dendritic cells among human PBMCs in vitro. DZ2002 (100 mu mol/L) also significantly suppressed TLR agonists-stimulated up-regulation in IL-6 and IL-23p19 production in murine BMDCs, and prevented Th17 differentiation and suppressed IL-17 secretion by the T cells in a BMDC-T cell co-culture system.Conclusion: DZ2002 effectively ameliorates lupus syndrome in NZB/W F1 mice by regulating TLR signaling-mediated antigen presenting cell (APC) responses.