Ji Jianjian, Fan Hongye, Li Fanlin, Li Xiaojing, Dong Guanjun, Gong Wei, Song Yuxian, Liu Fei, Hua Chunyan, Tan Renxiang, Dou Huan, Hou Yayi
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, PR China.
State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
Immunol Lett. 2015 Dec;168(2):355-65. doi: 10.1016/j.imlet.2015.10.017. Epub 2015 Nov 3.
Systemic lupus erythematosus (SLE) is an autoimmune disease with prominent chronic inflammatory aspects. Plasmacytoid dendritic cells (pDCs), which are the principal interferon-α (IFN-α)-producing cells, have known to be critically involved in SLE pathogenesis. Our previous research demonstrated that a benzenediamine derivative FC-99 possessed anti-inflammatory activities. However, the effects of FC-99 on SLE have not been investigated to date. In this study, we found that FC-99 attenuated lupus-like pathological symptoms and lupus nephritis as well as the expression of pro-inflammatory cytokines in kidneys of MRL/lpr mice. FC-99 also decreased both the total IgM, total IgG and anti-dsDNA IgG levels in sera and the activation of B cells in the PBMCs and spleens of MRL/lpr mice. Moreover, FC-99 inhibited the abnormal activation and number of pDCs from PBMCs and spleens and levels of IFN-α in MRL/lpr mice. Notably, FC-99 significantly suppressed the expression of IFN-inducible genes in peripheral blood mononuclear cells (PBMCs) and spleens from MRL/lpr mice. As expected, in vitro experiments demonstrated that FC-99 decreased both the activation and IFN-α production of pDCs and inhibited IRAK4 phosphorylation in pDCs upon TLR7 and TLR9 stimulation. We further confirm that the inhibition of FC-99 on B cell activation depended on level of pDCs-secreting IFN-α. These data indicate that FC-99 attenuated lupus-like syndrome in MRL/lpr mice related to suppression of pDC activation, especially pDCs-secreting IFN-α. This study suggests that FC-99 may be a potential therapeutic candidate for the treatment of SLE.
系统性红斑狼疮（SLE）是一种具有显著慢性炎症特征的自身免疫性疾病。浆细胞样树突状细胞（pDCs）是产生主要干扰素-α（IFN-α）的细胞，已知其在SLE发病机制中起关键作用。我们之前的研究表明，一种苯二胺衍生物FC-99具有抗炎活性。然而，迄今为止尚未研究FC-99对SLE的影响。在本研究中，我们发现FC-99减轻了MRL/lpr小鼠的狼疮样病理症状和狼疮性肾炎，以及肾脏中促炎细胞因子的表达。FC-99还降低了MRL/lpr小鼠血清中的总IgM、总IgG和抗双链DNA IgG水平，以及外周血单个核细胞（PBMCs）和脾脏中B细胞的活化。此外，FC-99抑制了MRL/lpr小鼠PBMCs和脾脏中pDCs的异常活化和数量以及IFN-α水平。值得注意的是，FC-99显著抑制了MRL/lpr小鼠外周血单个核细胞（PBMCs）和脾脏中IFN诱导基因的表达。正如预期的那样，体外实验表明，FC-99降低了pDCs的活化和IFN-α产生，并在TLR7和TLR9刺激后抑制了pDCs中IRAK4的磷酸化。我们进一步证实，FC-99对B细胞活化的抑制取决于pDCs分泌IFN-α的水平。这些数据表明，FC-99减轻了MRL/lpr小鼠的狼疮样综合征，这与抑制pDC活化，特别是分泌IFN-α的pDCs有关。本研究表明，FC-99可能是治疗SLE的潜在候选药物。
