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

Zheng-Wen He,Yan Chen,Yang-Hua Qin,Sheng-Ming Dai,Zhi-Wei Wang,Qian Shen

doi:10.1155/2013/596716

Abstract

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.

Highlights

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation and cartilage and bone destruction in multiple joints
When the cultured RA synovial fibroblasts (RASF) were stimulated with LPS (10 ng/mL) or High-mobility group box chromosomal protein 1 (HMGB1) (100 ng/mL) alone for 24 h, cell cycle analysis showed that the proportion of the cells in S phase significantly increased (Figures 1(a) and 1(b)), but no significant changes in cell proliferation rates were found (Figure 1(c))
HMGB1 has been identified as a potent proinflammatory cytokine that controls the activation and chemotaxis of inflammatory cells and stimulates the synthesis of proinflammatory cytokines

Summary

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation and cartilage and bone destruction in multiple joints. Synovial fibroblasts (SF) in RA are one of the dominant cell types in the terminal layer of the hyperplastic rheumatoid synovium and at the sites of invasion into the adjacent cartilage and bone. RA synovial fibroblasts (RASF) actively contribute to inflammation, angiogenesis, and matrix degradation by producing proinflammatory cytokines, proangiogenic factors, and matrix degrading enzymes [1,2,3]. Proinflammatory factors produced by immune cells and RASF further induce the secretion of matrix-degrading enzymes and proinflammatory cytokines by RASF, contributing to joint erosion and enhancing the inflammatory cycle in RA. Knowledge about the crosstalk between the aforementioned factors underlying the activation of RASF in RA is very limited

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Conclusion