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

摘要

Synovial fibroblasts (SF) play a central role in the inflammatory anddestructive process in rheumatoid arthritis (RA). High-mobilitygroup box chromosomal protein 1 (HMGB1) or lipopolysaccharide(LPS) alone failed to induce significant changes in proliferationof cultured SF from RA patients, but premixed HMGB1 with LPS(HMGB1-LPS) significantly facilitated SF proliferation. HMGB1alone failed to induce IL-6, MMP-3, and MMP-13 production incultured SF but greatly enhanced LPS-induced expression of IL-6,MMP-3, and MMP-13 at both mRNA and protein levels. HMGB1-LPSsynergistically upregulated TLR4 and receptor for advancedglycation endproducts (RAGE) expression on the surface of SF. Bothblockers of TLR4 and RAGE significantly inhibited the synergisticeffects of HMGB1-LPS on the production of IL-6 and MMPs, butblocking antibodies to TLR2 failed. HMGB1-LPS synergisticallyincreased intracellular levels of phosphorylated p38 andphosphorylated IκB. Furthermore, both NF-κB inhibitor Bay11-7085and p38 inhibitor SB203580 significantly suppressed the enhancedproduction of IL-6 and MMPs induced by HMGB1-LPS. In conclusion,HMGB1 acts in synergy with LPS to upregulate TLR4 and RAGEexpression 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-κBactivation.