A benzenediamine derivative fc-99 attenuates lupus-like syndrome in MRL/lpr mice related to suppression of pDC activation

Systemic lupus erythematosus (SLE) is an autoimmune disease with prominent chronic inflammatory aspects. Plasmacytoid dendritic cells (pDCs), which are the principal interferon-alpha (IFN-alpha)-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-alpha 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-alpha production of pDCs and inhibited IRAK4 phosphorylation in pDCs upon TLR7 and TLR9 stimulation. We further comfirm that the inhibition of FC-99 on B cell activation depended on level of pDCs-secreting IFN-alpha. These data indicate that FC-99 attenuated lupus-like syndrome in MRL/lpr mice related to suppression of pDC activation, especially pDCs-secreting IFN-alpha. This study suggests that FC-99 may be a potential therapeutic candidate for the treatment of SLE. (C) 2015 Elsevier B.V. All rights reserved.