Low molecular weight compounds which inhibit BAFF binding to its receptor, BR3, suppress activation of monocytes.

Abstract

Abstract Backgrounds and Purpose We found that the elevated expression of a BAFF receptor, BR3, in monocytes of patients with primary Sjögren’s syndrome (pSS) was involved in overproduction of IL-6 by BAFF-stimulated pSS monocytes. Additionally, the proportion of BR3-positive monocytes to total monocytes was positively and significantly correlated with the serum IgG level of pSS patients. In this study, we investigated the effects of the compounds, which block BAFF binding to BR3, on BAFF-induced IL-6 production in pSS monocytes. Methods High throughput screening (HTS) of a chemical library was carried out to search for compounds that block binding of soluble BAFF (sBAFF) to BR3. THP-1 and peripheral monocytes prepared from pSS patients were cultured in the presence of sBAFF and the binding inhibitors. IL-6 production by the cells was measured by ELISA. Results A total of 18,562 compounds were examined for inhibitory activities of sBAFF binding to BR3. To eliminate false positives, inhibitory activities of the HTS-hits against IL-6 production by sBAFF-stimulated THP-1 were measured. As a result, we discovered two pyrrolopyrimidine derivatives which showed substantial inhibition of sBAFF-binding. sBAFF-induced IL-6 production by pSS monocytes was significantly suppressed by these compounds in a dose dependent manner. Conclusion We have successfully discovered low molecular weight compounds which have inhibitory activities against BAFF signaling in monocytes.