A new benzenediamine derivative modulates Toll-like receptors-induced myeloid dendritic cells activation and ameliorates lupus-like syndrome in MRLlpr/lpr mice.
Modulators of the over-activation of myeloid dendritic cells (mDCs) by Toll-like receptors (TLRs) have an advantage in the treatment of systemic lupus erythematosus (SLE). This study was designed to evaluate the effects of FC-99, a novel benzenediamine derivative, on TLR-induced activation of mDCs, and to assess the efficacy of FC-99 in a murine model of SLE. In vitro, FC-99 inhibited the phenotypic (CD40 and MHC-II) and functional activation (IL-12 and CXCL10) of mDCs induced by TLR ligands. In vivo, MRLlpr/lpr mice displayed renal diseases associated with increased levels of proteinuria and immunoglobulin, which were ameliorated by FC-99. Enhanced accumulation and activation of mDCs in lymphoid organs was also impaired by FC-99. Additionally, FC-99 inhibited the activation of IκB-α and upregulated the expression of TNFα-induced protein 3 (TNFAIP3) in vitro and in vivo. These results indicate that FC-99 modulates TLR-induced activation of mDCs and ameliorates lupus-like syndrome in MRLlpr/lpr mice. This effect is closely associated with the inhibition of IκB-α and upregulation of TNFAIP3.
Laboratory Animal Center, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China.
Sheng
S
Gao
School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China.
Yongsheng
Y
Gong
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, Jiangsu Province, China.
Jianjian
J
Ji
School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China.
Linbo
L
Yuan
School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China.
Liping
L
Han
School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China.
Yimin
Y
Guo
School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China.
Xiaofang
X
Fan
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, Jiangsu Province, China. Electronic address: yayihou@nju.edu.cn.
Yayi
Y
Hou
School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou 325035, Zhejiang Province, China. Electronic address: florshine@163.com.
Chunyan
C
Hua
D000818:Animals; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D015195:Drug Design; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D056747:Immunomodulation / Q000187:drug effects; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D022423:Myeloid Cells / Q000166:cytology*; D000072000:NF-KappaB Inhibitor alpha / Q000037:antagonists & inhibitors; D010655:Phenylenediamines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051193:Toll-Like Receptors / Q000378:metabolism*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000378:metabolism
C000598432:N1-((4-methoxy)methyl)-4-methyl-1,2-benzenediamine; D010655:Phenylenediamines; D051193:Toll-Like Receptors; D000072000:NF-KappaB Inhibitor alpha; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
FC-99; SLE; TLRs; mDCs