title: Immune complexes activate human endothelium involving the cell-signaling HMGB1-RAGE axis in the pathogenesis of lupus vasculitis.
abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the formation of immune complexes (ICs), which contain a complex mixture of autoantigens nucleic acids, nucleic acids-associated proteins and corresponding autoantibodies. In SLE, ICs are deposited in multiple organs. Vasculopathy and vasculitis in SLE are typical complications and are associated with deposition of ICs on endothelium, endothelial activation and inflammatory cell infiltration. However, the effects of ICs on endothelial cells and the mechanisms involved remain unclear. In this study, we have demonstrated for the first time that ICs upregulated cell surface expression of the receptor for advanced glycation end products (RAGE), the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), increased the secretion of the chemokines interleukin 8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), the proinflammatoy cytokines interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α) and promoted the activation of the transcription factor NF-κB p65 in human endothelial cells (P<0.05). ICs also increased transendothelial migration of monocytes (P<0.05). One of the mechanisms underlying these activating effects of ICs on human endothelial cells involves cell signaling by high-mobility group box 1 protein (HMGB1)-RAGE axis, as these effects can be partially blocked by HMGB1 A-box, soluble RAGE (sRAGE), SB203580, PD98059, Bay 117082 (P<0.05) and co-treatment with these agents (P<0.05). In conclusion, ICs elicit proinflammatory responses in human endothelial cells and alter their function involving cellular signaling via the HMGB1-RAGE axis in the pathogenesis of SLE vasculitis.
authors: Central Laboratory, Provincial Hospital Affiliated to Shandong University, Jinan 250021, People's Republic of China.
authors: Wenping
authors: W
authors: Sun
authors: Yulian
authors: Y
authors: Jiao
authors: Bin
authors: B
authors: Cui
authors: Xuejun
authors: X
authors: Gao
authors: Yu
authors: Y
authors: Xia
authors: Yueran
authors: Y
authors: Zhao
mesh_terms: D000936:Antigen-Antibody Complex / Q000378:metabolism*; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D020945:Lupus Vasculitis, Central Nervous System / Q000276:immunology*; D009000:Monocytes / Q000502:physiology; D009570:Nitriles; D011725:Pyridines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D015398:Signal Transduction; D013450:Sulfones; D051996:Transcription Factor RelA / Q000378:metabolism; D057705:Transendothelial and Transepithelial Migration; D020298:U937 Cells; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000936:Antigen-Antibody Complex; D016207:Cytokines; D005419:Flavonoids; D024243:HMGB1 Protein; D007093:Imidazoles; D009570:Nitriles; D011725:Pyridines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013450:Sulfones; D051996:Transcription Factor RelA; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D048049:Extracellular Signal-Regulated MAP Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one