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Background and Purpose: B cell activating factor belonging to the TNF superfamily (BAFF) is indispensable for proliferation, differentiation and survival of B cells. Several lines of evidence suggest that elevated production of BAFF seemed to be involved in the development of autoimmune diseases such as Sjögren's syndrome (SS). In our previous study, we investigated that BAFF and IL-6 were abnormally produced in SS monocytes upon stimulation with IFN-gamma. In the present study, we investigated a regulatory mechanism of the production of these cytokines in SS monocytes. Materials and Methods: Peripheral monocytes prepared from SS patients and normal individuals were stimulated with IFN-gamma or soluble BAFF (sBAFF). The expression levels of sBAFF, IL-6 and transcription factors were measured by ELISA and/or semi-quantitative RT-PCR. Results and Discussion: IFN-gamma remarkably induced the production of sBAFF and IL-6 in SS monocytes. The production of IL-6 was significantly suppressed by an anti-BAFF antibody. In addition, stimulation of SS monocytes with sBAFF induced robust increase in the production of IL-6. These data suggest that the production of IL-6 in monocytes is induced partly through a signal transduction pathway triggered by sBAFF. We found that the expression levels of several transcription factors were aberrantly elevated in SS monocytes as compared with normal monocytes. These data strongly suggest that sBAFF produced in monocytes acts in an autocrine or paracrine fashion to activate the expression of the IL-6 gene, and that signal transduction triggered by sBAFF may be impaired in SS monocytes. This aberration may underlie the development of SS.

Objectives: Polycystic ovarian syndrome (PCOS) is the most common endocrine and metabolic disorders among women of reproductive age. It has been associated with cardio-renal disturbance. In fact, cardiovascular disease and chronic kidney disease remain the major cause of disease burden worldwide. Mineralocorticoid receptor activation has been demonstrated in various pathological conditions, including cardiovascular and renal dysfunction. Spironolactone is a mineralocorticoid receptor blocker that regulates metabolic-related functions. However, the impact of spironolactone (LSPL), on PCOS associated cardio-renal disorder is unknown. Therefore, the present study hypothesized that LSPL would ameliorate cardio-renal disorders in experimental PCOS animal. Materials and Methods:Female Wistar rats that were eight-week-old were allotted into three groups. The control group received vehicle (distilled water; p.o.), LET-treated group designated as PCOS group received letrozole (1 mg/kg; p.o.), while PCOS+LSPL received a combination of letrozole and LSPL (0.25 mg/kg, p.o.). The treatment was done once daily for 21 days uninterrupted. Results:The experimental PCOS rats were characterized with insulin resistance as well as, elevated testosterone and LH/FSH with a significant increase in cardiac and renal lipid profile, oxidative stress, inflammatory biomarkers (NF-kappaB and TNF-alpha), LDH and lactate content, and decrease in cardiac and renal antioxidant system (GPX and GSH) compared with the control rats. There was also a significant increase in cardiac GGT but not renal GGT activity in PCOS animals. In addition, immunohistochemical assessment of cardiac and renal tissue showed severe expression of inflammasome and moderate expression of BAX in animals with PCOS. Nevertheless, these perturbations were attenuated following the administration of LSPL. Conclusion:Collectively, the present results suggests that low dose spironolactone attenuates PCOS-associated cardio-renal disorders by reduction of oxidative stress and BAX/Inflammasome expression.

Backgrounds and Purpose We have demonstrated that the elevated expression of BAFF receptor (BR3) on monocytes is involved in the overproduction of IgG by B cells in patients with primary Sjögren’s syndrome (pSS) which is often accompanied with hypergammaglobulinemia. We discovered a low molecular weight compound, BIK13, which inhibits binding of BAFF to BR3, by our original high-throughput screening system. We found that BIK-13 suppressed IL-6 production by BAFF-stimulated pSS monocytes. In this study, we investigated inhibitory effects of BIK-13 on B cell functions. Methods PBMCs were cultured with a B cell-stimulants cocktail, such as anti-IgM and CD40 antibodies, human IL-21 and human BAFF, in the presence of BIK-13. B cell-differentiation was monitored through analysis of the expression levels of CD19/CD38/IgD and activation-induced cytidine deaminase (AID) by FACS and qPCR, respectively. The amounts of IL-6 and IgG produced in vitro by the cells were measured by ELISA. Results Increased production of IgG and IL-6 by PBMC upon stimulation with B cell-stimulants was suppressed by BIK13 in a dose dependent manner. FACS analysis indicated that differentiation of B cells into plasma blasts and/or plasma cells was inhibited by BIK-13. In addition, the expression level of AID was also suppressed by the compound, suggesting that the IgG class switching was impaired. Conclusion These data collectively suggest that BIK-13 suppresses the B cell functions and may provide a novel therapeutic possibility to treat autoimmune diseases such as pSS.

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