Characterization of monocyte tissue factor activity induced by IgG antiphospholipid antibodies and inhibition by dilazep.
Increasing evidence suggests that autoantibodies directly contribute to hypercoagulability in the antiphospholipid syndrome (APS). One proposed mechanism is the antibody-induced expression of tissue factor (TF) by blood monocytes. Dilazep, an antiplatelet agent, is an adenosine uptake inhibitor known to block induction of monocyte TF expression by bacterial lipopolysaccharide. In the current study we characterized the effects of immunoglobulin G (IgG) from patients with APS on monocyte TF activity and investigated whether dilazep is capable of blocking this effect. IgG from 13 of 16 patients with APS significantly increased monocyte TF activity, whereas normal IgG had no effect. Time-course experiments demonstrated that APS IgG-induced monocyte TF mRNA levels were maximal at 2 hours and TF activity on the cell surface was maximal at 6 hours. Dilazep inhibited antibody-induced monocyte TF activity in a dose-dependent fashion but had no effect on TF mRNA expression. The effect of dilazep was blocked by theophylline, a nonspecific adenosine receptor antagonist. In conclusion, IgG from certain patients with APS induce monocyte TF activity. Dilazep inhibits the increased expression of monocyte TF activity at a posttranscriptional level, probably by way of its effect as an adenosine uptake inhibitor. Pharmacologic agents that block monocyte TF activity may be a novel therapeutic approach in APS.
Zhou
Hong
H
Division of Rheumatology and Immunology, CB#7280, Rm 3330 Thurston Bldg, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7280, USA. roubey@med.unc.edu
Wolberg
Alisa S
AS
Roubey
Robert A S
RA
D017152:Antibodies, Antiphospholipid / Q000276:immunology* / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000276:immunology; D001800:Blood Specimen Collection; D004109:Dilazep / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D053482:beta 2-Glycoprotein I
D017152:Antibodies, Antiphospholipid; D000911:Antibodies, Monoclonal; D006023:Glycoproteins; D007140:Immunoglobulin Fab Fragments; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D053482:beta 2-Glycoprotein I; D013925:Thromboplastin; D004109:Dilazep