Aberrant Expression of BAFF Receptor (BR3) in Peripheral Monocytes of Patients with Primary Sjögren’s Syndrome Impacts Abnormal Activation of BAFF Signaling Through IKK-Alphaand IKK-Beta

Keiko Yoshimoto¹, Maiko Tanaka², Masako Kojima², Hideko Ogata², Hideto Kameda¹, Katsuya Suzuki¹, Tohru Abe³ and Tsutomu Takeuchi⁴, ¹Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan, ²Division of Rheumatology and Clinical Immunology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan, ³Dept Int Med Saitama Med Ctr, Saitama Medical School, Kawagoe-shi Saitama, Japan, ⁴Rheumatology, Keio University School of Medicine, Tokyo, Japan

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: BAFF, interleukins (IL), monocytes and signal transduction

Session Information

Title: Cytokines, Mediators, and Gene Regulation

Session Type: Abstract Submissions (ACR)

Background/Purpose: 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). BAFF is a ligand for three TNF-receptor family members; i.e., BAFF receptor (BR3), TACI and BCMA. Several lines of evidence demonstrate that BR3 is the receptor that mediates BAFF-dependent B cell biology and that BAFF activates alternative NF-kB signaling in B cells. However, the regulatory mechanisms of BAFF signaling in other immune cells, such as monocytes, are not well understood. In our previous study, we revealed that BAFF induced robust increase in the production of IL-6 by pSS monocytes. We also found that the expression levels of BR3 and several transcription factors such as NF-IL-6 and NF-kB2 were enhanced in pSS monocytes compared to normal monocytes. These data suggest that BAFF signaling is abnormal in pSS monocytes. The purpose of the present study is to elucidate these possible abnormalities.

Methods: Whole blood was prepared from pSS patients and age-matched normal individuals, and the expression level of BR3 on monocytes was analyzed by FACS. Peripheral monocytes were stimulated in vitro with soluble BAFF (sBAFF), and the production of IL-6 by the cells was measured by ELISA. The expression levels of IKK-alpha and IKK-beta, which are involved in NF-kB pathways, were analyzed by western blotting analysis.

Results: In accordance with our previous findings with quantitative PCR, FACS analysis showed that the expression level of BR3 was significantly elevated in pSS monocytes compared to normal monocytes. Interestingly, the expression level of BR3 on monocytes was positively correlated with the amount of IL-6 produced by pSS monocytes triggered by sBAFF. When the monocytes were cultured with sBAFF in the presence of NF-kB activation inhibitor, the production of IL-6 by the cells was strongly suppressed in a dose-dependent manner. In addition, phosphorylation level of IKK-alpha was elevated in pSS monocytes compared to normal monocytes without stimulation, whereas that of IKK-beta was not significantly different between pSS and normal monocytes. Moreover, phosphorylation levels of IKK-alpha and IKK-beta in the monocytes were enhanced upon stimulation with sBAFF.

Conclusion: BAFF acts through BR3 to activate the expression of the IL-6, and that IKK-alpha and IKK-beta are involved in the signal transduction pathway triggered by sBAFF.

Disclosure:

K. Yoshimoto,
None;

M. Tanaka,
None;

M. Kojima,
None;

H. Ogata,
None;

H. Kameda,
None;

K. Suzuki,
None;

T. Abe,
None;

T. Takeuchi,
None.

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