Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Abnormalities in a JAK-STAT Pathway Are Involved in the Aberrant Production of IL-6 by BAFF-Stimulated Peripheral Monocytes of Patients with Primary Sjgren's Syndrome.
Yoshimoto1, Keiko, Tanaka1, Maiko, Kojuma1, Masako, Ogata1, Hideko, Kameda1, Hideto, Abe2, Tohru, Takeuchi1, Tsutomu
It has been reported that B cell activating factor belonging to the TNF family (BAFF) and IL-6 are involved in the development of primary Sjögren's syndrome (pSS). BAFF is mainly expressed in monocytes and dendritic cells, and regulates proliferation, differentiation and survival of B cells, which play a pivotal role in the production of autoantibodies and hence in the development of autoimmune diseases. IL-6 is produced by many types of cells including monocytes, and promotes differentiation of B cells. In our previous study, we found that soluble BAFF (sBAFF) abnormally induced the production of IL-6 by peripheral pSS monocytes cultured in vitro.In the present study, we investigated a regulatory mechanism for the production of IL-6 by BAFF-stimulated monocytes and possible abnormalities of pSS monocytes.
Peripheral monocytes were prepared from pSS patients and age-matched normal individuals. The cells were stimulated in vitro with sBAFF in the presence or absence of inhibitors against several protein kinases, i.e., JAK2, JAK3, p38MAPK and JNK. The production of IL-6 by the cells was measured by ELISA. The expression levels of the kinases were analyzed by quantitative PCR.
pSS monocytes produced substantial amount of IL-6 even in the absence of stimulation, while normal monocytes produced only marginal amount of IL-6. The production of IL-6 by the cells was increased when the cells were stimulated with sBAFF. The increase was especially remarkable for pSS monocytes as compared with normal monocytes. The elevated productions of IL-6 by the cells were significantly suppressed in a dose dependent manner by inhibitors against protein kinases, such as JAK2, JAK3, p38MAPK and JNK, thus far examined. Among the inhibitors, a JAK3 inhibitor showed the highest effect. Quantitative PCR analysis indicated that no significant difference was observed between normal and pSS monocytes in the expression level of JAK3. However, stimulation of pSS monocytes with sBAFF strongly induced the expression of JAK3 while normal monocytes did not significantly respond to the stimulation. Similarly, the expression levels of STAT3 and STAT4 in monocytes were increased upon stimulation with sBAFF, and the increase was higher in pSS monocytes than the control. The increase was remarkable for STAT4 as compared with STAT3.
Our data suggest that a JAK3-STAT4 pathway may be involved in the production of IL-6 by sBAFF-stimulated peripheral monocytes. In addition, abnormalities in the induction of JAK3 and STAT4 may be responsible for the abnormal responses of pSS monocytes to sBAFF. These abnormalities may be involved in the pathogenesis of pSS.
To cite this abstract, please use the following information:
Yoshimoto, Keiko, Tanaka, Maiko, Kojuma, Masako, Ogata, Hideko, Kameda, Hideto, Abe, Tohru, et al; Abnormalities in a JAK-STAT Pathway Are Involved in the Aberrant Production of IL-6 by BAFF-Stimulated Peripheral Monocytes of Patients with Primary Sjgren's Syndrome. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :44