P081 JAK3 is involved in BAFF-mediated abnormal production of IL-6 by peripheral monocytes of patients with primary Sjögren’s syndrome
Introduction B cell activating factor belonging to the TNF superfamily (BAFF) regulates proliferation, differentiation and survival of B cells. Several lines of evidence have been reported that elevated production of BAFF seemed to be involved in the development of autoimmune diseases such as primary Sjogren’s syndrome (pSS). In our previous study, we revealed that pSS monocytes produced significantly higher amount of IL-6 than normal monocytes upon stimulation with soluble BAFF (sBAFF). These data suggest that the production of IL-6 by monocytes in induced partly through a signal transduction pathway triggered by sBAFF. Since IL-6 may be involved in the production of autoantibodies by B cells, elucidation of the regulatory mechanism of 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. In the present study, we investigated possible abnormalities of BAFF signaling pathways in pSS monocytes. Methods The expression levels of BAFF receptor (BAFF-R) on peripheral monocytes of pSS patients (n = 10) and age-matched normal individuals (n = 8) were analyzed by FACS and quantitative PCR. The monocytes were stimulated in vitro with sBAFF in the presence or absence of inhibitors against JAK2 (AG490) and JAK3 (WHI-P131), and the production of IL-6 by the cells was measured by ELISA. The expression levels of the kinases were analyzed by quantitative PCR. Results Quantitative PCR showed that the expression level of BAFF-R was significantly elevated in pSS 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 were positive. These data suggest that the increased expression of BAFF-R in pSS monocytes was attributed to an increase in the population of BAFF-R-positive cells among monocytes of pSS patients. Notably, the expression of level of BAFF-R varied among pSS patients and was positively correlated with the IL-6 production by monocytes. We found that a JAK3 inhibitor showed strong suppressive effect on the production of IL-6 by the monocytes in a dose dependent manner. These data strongly suggest that sBAFF activates monocytes to induce IL-6 production through a JAK pathway. Interestingly, stimulation of pSS monocytes with sBAFF induced the expression of JAK3 while normal monocytes did not significantly respond to the stimulation. Conclusion Though the contribution of this induction to the overproduction of IL-6 remains obscure, we believe that these abnormalities as well as the up-regulation of BAFF-R underlie the abnormal production of IL-6 by pSS monocytes.