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Importance of C-Reactive Protein in Regulating Monocyte Tissue Factor Expression in
Patients with Inflammatory Rheumatic Diseases
HONG CAI, CHANGJIE SONG, IRWIN GEOK SAN LIM, STEVEN A. KRILIS, CAROLYN L. GECZY, and H. PATRICK McNEIL ABSTRACT. Objective. To determine the relationship between plasma C-reactive protein (CRP) concentrations and monocyte tissue factor (TF) expression induced in vitro by combinations of CRP, ß2-glycoprotein I (ß2-GPI), and lipopolysaccharide (LPS). Methods. Peripheral blood mononuclear cells (PBMC) from 26 healthy individuals and 31 patients with inflammatory rheumatic diseases (IRD) were cultured with combinations of CRP, purified or recombinant ß2-GPI, and LPS and monocyte TF procoagulant activity, TF antigen, and TF mRNA were measured. Results were examined against plasma CRP levels. Results. Monocytes from patients with IRD expressed significantly more TF when stimulated with CRP compared to normal monocytes (p = 0.002). An incremental positive correlation was observed between plasma CRP levels and TF induced by CRP or ß2-GPI. Significantly more TF was induced with CRP combined with ß2-GPI, compared to ß2-GPI alone, either with costimulation or CRP priming. Conversely, when combined with LPS, ß2-GPI suppressed TF induction in a dose-dependent manner on normal PBMC but not on PBMC from patients with IRD. The loss of suppression correlated strongly with plasma CRP levels. Conclusion. This study shows a remarkably consistent effect of CRP on monocyte TF expression. Systemic inflammation associated with elevated plasma CRP conferred a phenotype on PBMC, whereby incremental priming with respect to TF expression (induced by CRP itself or ß2-GPI) was apparent, and ß2-GPI-mediated inhibition of TF expression induced by LPS was incrementally lost. CRP regulation of monocyte TF could contribute to the higher than expected atherosclerotic vascular disease seen in patients with IRD. (J Rheumatol 2005;32:1224–31) Key Indexing Terms: RHEUMATOID ARTHRITIS From the Inflammatory Diseases Research Unit, School of Medical Sciences, University of New South Wales (UNSW); Department of Rheumatology, Prince of Wales Hospital; and Department of Immunology, Allergy and Infectious Disease, St. George Hospital, Sydney, Australia. Supported by grants from the National Health and Medical Research Council of Australia and the Arthritis Foundation of Australia. H. Cai, MB, MM, PhD, Research Assistant; C. Song, MB, MM, Doctoral Student, School of Medical Sciences, UNSW; I.G.S. Lim, MB, BS, Senior Registrar, Prince of Wales Hospital; S.A. Krilis, MB, BS, PhD, Professor, Director, Department of Immunology, Allergy and Infectious Disease, St. George Hospital; C.L. Geczy, BSc, PhD, Professor, School of Medical Sciences, UNSW; H.P. McNeil, MB, BS, PhD, Associate Professor, Prince of Wales Clinical School, UNSW. Address reprint requests to Prof. H.P. McNeil, Office of Medical Education, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia 2052. E-mail: P.McNeil@unsw.edu.au Accepted for publication February 23, 2005. |