HMGB1 Acts in Synergy with Lipopolysaccharide in Activating Rheumatoid Synovial Fibroblasts via p38 MAPK and NF-κB Signaling Pathways
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 p...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2013-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2013/596716 |
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| Summary: | 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. |
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| ISSN: | 0962-9351 1466-1861 |