Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>System lupus erythematosus (SLE) is a complex autoimmune disease with high mortality and morbidity. A targeted therapy is desirable for personalized medication of SLE. Recently we used a novel Activity-based Kinome Screening and identified several novel signaling molecules which are up- or downregulated in murine lupus. Totally we screened 196 kinases in spleens from two lupus mouse models, B6.Sle1.Sle3 and MRL.lpr. Compared to the B6 control, PLK1 and its upstream regulator Aurora A exhibited significantly increased activities. We further found the activation of both Aurora-A and PLK1 were significantly upregulated in splenic B220+ B cells of lupus mice MRL.lpr. We found a PLK1 specific inhibitor NMS-P064 ameliorated splenomegaly (P &lt; 0.05), anti-dsDNA antibody production (P &lt; 0.001), proteinuria and BUN, and renal pathology GN score in MRL.lpr. In addition, we found IL-6, IL-17 and kidney injury molecule 1 (KIM-1) were significantly decreased in the serum of MRL.lpr mice after PLK1 inhibition. In vitro, after 24 h stimulation of splenocytes with CD40 ligand, IL-6 secretion was significantly reduced upon PLK1 blockade (P &lt; 0.05). Whereas IL-10 secretion was significantly increased in anti-IgM Fab’ fragment stimulated splenocytes upon PLK1 blockade. Given the phosphorylation of PLK1 was significantly increased on Thr 210 in murine lupus, it is possible that this could be the consequence of the direct phosphorylation of PLK1 by Aurora A. Taken together, PLK1 may contribute to the pathogenesis of lupus via Aurora-A/PLK1 signaling cascade and might be a potential therapeutic target of lupus.</jats:p>