title: Serum amyloid A induces monocyte tissue factor.
abstract: C-reactive protein (CRP) and serum amyloid A (SAA) increase in the blood of patients with inflammatory conditions and CRP-induced monocyte tissue factor (TF) may contribute to inflammation-associated thrombosis. This study demonstrates that SAA is a potent and rapid inducer of human monocyte TF. SAA induced TF mRNA in PBMC within 30 min and optimal procoagulant activity within 4 h, whereas CRP (25 mug/ml)-induced activity was minimal at this time. Unlike CRP, SAA did not synergize with LPS. Procoagulant activity was inhibited by anti-TF and was dependent on factors VII and X, and TF Ag levels were elevated on CD14(+) monocytes. Responses were optimal with lymphocytes, although these were not obligatory. Inhibitor studies indicate activation of NF-kappaB through the ERK1/2 and p38 MAPK pathways; the cyclo-oxygenase pathway was not involved. SAA-induced TF was partially inhibited by high-density lipoprotein, but not by low-density lipoprotein or by apolipoprotein A-I. SAA is a ligand for the receptor for advanced glycation end products (RAGE), and TF generation was suppressed by approximately 50% by a RAGE competitor, soluble RAGE, and by approximately 85% by anti-RAGE IgG. However, another RAGE ligand, high mobility group box-1 protein, capable of inducing monocyte chemotactic protein-1 mRNA in 2 h, did not induce TF within 24 h. Cross-linking studies confirmed SAA binding to soluble RAGE. Elevated SAA is a marker of disease activity in patients with rheumatoid arthritis, and PBMC from patients with rheumatoid arthritis were more sensitive to SAA than normals, suggesting a new link between inflammation and thrombosis.
authors.affiliation: Inflammatory Diseases Research Unit, School of Medical Sciences, University of New South Wales, Sydney, Australia.
authors.forename: Hong
authors.initials: H
authors.lastname: Cai
authors.forename: Changjie
authors.initials: C
authors.lastname: Song
authors.forename: Ikuko
authors.initials: I
authors.lastname: Endoh
authors.forename: Jesse
authors.initials: J
authors.lastname: Goyette
authors.forename: Wendy
authors.initials: W
authors.lastname: Jessup
authors.forename: S Ben
authors.initials: SB
authors.lastname: Freedman
authors.forename: H Patrick
authors.initials: HP
authors.lastname: McNeil
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Geczy
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood; D002097:C-Reactive Protein; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008074:Lipoproteins / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D019851:Thrombophilia; D013925:Thromboplastin / Q000235:genetics*
chemical_list: D008074:Lipoproteins; D016328:NF-kappa B; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D000685:Serum Amyloid A Protein; D002097:C-Reactive Protein; D013925:Thromboplastin