title: Anti-inflammatory effects of high-dose IgG on TNF-α-activated human coronary artery endothelial cells.
abstract: High-dose infusion of IgG (IVIG) is used to treat autoimmune and inflammatory diseases, including Kawasaki disease (KD). Although the immunomodulatory effects of IVIG on blood cells such as macrophages have been well studied, its effects on tissue cells remain unclear. Here, we show that high-dose IgG specifically and completely inhibited TNF-α-induced, but not IL-1β-induced, secretion of proinflammatory cytokines such as G-CSF and IL-6 by cultured human coronary artery endothelial cells (HCAECs). High-dose IgG did not inhibit TNF-α-mediated early signaling events of the NF-κB and MAPK pathways but it potently inhibited gene expression of G-CSF and IL-6 12 h after TNF-α-stimulation. Interestingly, suppression of the G-CSF and IL-6 gene expression correlated closely with functional inhibition of a transcription factor, C/EBPδ, whose binding sites in the promoters of G-CSF and IL-6 have been shown to be critical for their transcriptional activation. Furthermore, the inhibitory effect of intact IgG on HCAECs was exerted mainly via its F(ab')(2)  fragment, and not its Fc fragment. These findings suggest that the clinical effects of IVIG on KD patients are at least in part due to its direct anti-inflammatory effects on the coronary endothelium, which is a major lesion site in the pathogenesis of KD.
authors.affiliation: Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan. amatsuda@nch.go.jp
authors.forename: Akio
authors.initials: A
authors.lastname: Matsuda
authors.forename: Hideaki
authors.initials: H
authors.lastname: Morita
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Unno
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Saito
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hirao
authors.forename: Koji
authors.initials: K
authors.lastname: Munechika
authors.forename: Jun
authors.initials: J
authors.lastname: Abe
mesh_terms: D051743:CCAAT-Enhancer-Binding Protein-delta / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology*; D005786:Gene Expression Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000008:administration & dosage*; D053583:Interleukin-1beta / Q000276:immunology; D015850:Interleukin-6 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009080:Mucocutaneous Lymph Node Syndrome / Q000276:immunology / Q000628:therapy; D016328:NF-kappa B / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D007140:Immunoglobulin Fab Fragments; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051743:CCAAT-Enhancer-Binding Protein-delta; D016179:Granulocyte Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases