Background B cell activating factor belonging to the TNF superfamily (BAFF) regulates proliferation, differentiation and survival of B cells and plays a pivotal role in the pathogenesis of autoimmune diseases such as primary Sjögren’s syndrome (pSS). Several lines of evidence have suggested that elevated production of BAFF is involved in the development of pSS. In our previous study, we revealed that IFN-gamma remarkably induced the production of BAFF and IL-6 by pSS monocytes and that BAFF induced robust production of IL-6 by these cells. These data strongly suggest that the production of IL-6 in monocytes is induced through a signal transduction pathway triggered by BAFF. On the other hand, IFN-gamma and BAFF provoked only modest responses in normal monocytes. Therefore, elucidation of the regulatory mechanism which underlies the aberrant production of IL-6 by pSS monocytes is important not only to understand the mechanism of pathogenesis of pSS, but also to explore therapeutic possibilities to treat the disease.
Objectives We investigated the expression level of a BAFF receptor (BAFF-R) in pSS monocytes and possible abnormalities of BAFF signaling pathways in these cells.
Methods Peripheral monocytes from pSS patients and age-matched normal individualswere stimulated in vitro with soluble BAFF (sBAFF) in the presence or absence of inhibitors against JAK2 and JAK3. The expression level of BAFF-R in the cells was analyzed by FACS and quantitative PCR. ELISA was employed to measure the production of IL-6 by the cells. The expression levels of the JAK2 and JAK3 were analyzed by quantitative PCR.
Results Quantitative PCR analysis revealed that the expression level of BAFF-R was significantly elevated in SS monocytes (2.1-fold) compared to normal monocytes. In accordance with these data, FACS analysis indicated that approximately 60% of pSS monocytes were BAFF-R-positive while only about 25% of normal monocytes expressed BAFF-R. On the other hand, there were no significant differences between pSS patients and normal individuals in the population of BAFF-R-positive B and T cells. Moreover, the expression level of BAFF-R was positively correlated with the production of IL-6 among monocytes prepared from pSS patients enrolled in this study. We found that a JAK3 inhibitor (WHI-P131) showed strong suppressive effect on the induction of IL-6 in a dose dependent manner. Interestingly, stimulation of pSS monocytes with sBAFF strongly induced the expression of JAK3 while normal monocytes did not significantly respond to the stimulation.
Conclusions BAFF activates the expression of the IL-6 through a JAK pathway in monocytes and that the expression of BAFF-R and JAK3 is abnormally regulated in pSS monocytes.
Disclosure of Interest None Declared
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.