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Mediators of Inflammation
Volume 2013 (2013), Article ID 596716, 10 pages
Research Article

HMGB1 Acts in Synergy with Lipopolysaccharide in Activating Rheumatoid Synovial Fibroblasts via p38 MAPK and NF-κB Signaling Pathways

1Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China
2Department of Rheumatology & Immunology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China
3Department of Orthopedics, Changhai Hospital, Second Military Medical University, Shanghai 200433, China

Received 30 June 2013; Revised 5 September 2013; Accepted 21 September 2013

Academic Editor: Eric F. Morand

Copyright © 2013 Zheng-Wen He et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Synovial fibroblasts (SF) play a central role in the inflammatory and destructive process in rheumatoid arthritis (RA). High-mobility group box chromosomal protein 1 (HMGB1) or lipopolysaccharide (LPS) alone failed to induce significant changes in proliferation of cultured SF from RA patients, but premixed HMGB1 with LPS (HMGB1-LPS) significantly facilitated SF proliferation. HMGB1 alone failed to induce IL-6, MMP-3, and MMP-13 production in cultured SF but greatly enhanced LPS-induced expression of IL-6, MMP-3, and MMP-13 at both mRNA and protein levels. HMGB1-LPS synergistically upregulated TLR4 and receptor for advanced glycation endproducts (RAGE) expression on the surface of SF. Both blockers of TLR4 and RAGE significantly inhibited the synergistic effects of HMGB1-LPS on the production of IL-6 and MMPs, but blocking antibodies to TLR2 failed. HMGB1-LPS synergistically increased intracellular levels of phosphorylated p38 and phosphorylated IκB. Furthermore, both NF-κB inhibitor Bay11-7085 and p38 inhibitor SB203580 significantly suppressed the enhanced production of IL-6 and MMPs induced by HMGB1-LPS. In conclusion, HMGB1 acts in synergy with LPS to upregulate TLR4 and RAGE expression on the surface of SF in RA and then to augment IL-6, MMP-3, and MMP-13 production, which depends on p38 MAPK and NF-κB activation.