title: HMGB1 acts in synergy with lipopolysaccharide in activating rheumatoid synovial fibroblasts via p38 MAPK and NF-κB signaling pathways.
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 I κ B. Furthermore, both NF- κ B 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.
authors.affiliation: Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China ; Department of Rheumatology & Immunology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China.
authors.forename: Zheng-Wen
authors.initials: ZW
authors.lastname: He
authors.forename: Yang-Hua
authors.initials: YH
authors.lastname: Qin
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Qian
authors.initials: Q
authors.lastname: Shen
authors.forename: Sheng-Ming
authors.initials: SM
authors.lastname: Dai
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008875:Middle Aged; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D013583:Synovial Membrane / Q000166:cytology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C416282:BAY 11-7085; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C508600:IL6 protein, human; D007093:Imidazoles; D015850:Interleukin-6; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D009570:Nitriles; D011725:Pyridines; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013450:Sulfones; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C093642:SB 203580