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* Department of Pathology, Division of General Pathology, and
Department of Clinical and Experimental Medicine, Division of Rheumatology, University of Verona, Verona, Italy;
Department of Pathology, Spedali Civili, University of Brescia, Brescia, Italy;
Amgen, Thousand Oaks, CA 91301;
¶ Human Genome Sciences, Rockville, MD 20850;
|| CoGenesys, Rockville, MD 20850;
# Fondazione Humanitas per la Ricerca, Rozzano, Italy; and
** School of Biological Sciences, University of Liverpool, Liverpool, United Kingdom
TNF-like cytokine (TL1A) is a newly identified member of the TNF superfamily of ligands that is important for T cell costimulation and Th1 polarization. However, despite increasing information about its functions, very little is known about expression of TL1A in normal or pathological states. In this study, we report that mononuclear phagocytes appear to be a major source of TL1A in rheumatoid arthritis (RA), as revealed by their strong TL1A expression in either synovial fluids or synovial tissue of rheumatoid factor (RF)-seropositive RA patients, but not RF–/RA patients. Accordingly, in vitro experiments revealed that human monocytes express and release significant amounts of soluble TL1A when stimulated with insoluble immune complexes (IC), polyethylene glycol precipitates from the serum of RF+/RA patients, or with insoluble ICs purified from RA synovial fluids. Monocyte-derived soluble TL1A was biologically active as determined by its capacity to induce apoptosis of the human erythroleukemic cell line TF-1, as well as to cooperate with IL-12 and IL-18 in inducing the production of IFN-
by CD4+ T cells. Because RA is a chronic inflammatory disease with autoimmune etiology, in which ICs, autoantibodies (including RF), and various cytokines contribute to its pathology, our data suggest that TL1A could be involved in its pathogenesis and contribute to the severity of RA disease that is typical of RF+/RA patients.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants (to M.A.C.) from Ministero dell’Istruzione, dell’Università e della Ricerca (Progetti di Rilevante Interesse Nazionale 2005, Fondo di Investimento per la Ricerca di Base, and 60%), Fondazione Cassa di Risparmio, and Associazione Italiana per la Ricerca sul Cancro.
2 Address correspondence and reprint requests to Dr. Marco A. Cassatella, Division of General Pathology, Department of Pathology, Strada Le Grazie 4, Verona, Italy. E-mail address: marco.cassatella{at}univr.it
3 Abbreviations used in this paper: RA, rheumatoid arthritis; IC, immune complex; RF, rheumatoid factor; SF, synovial fluid; TL1A, TNF-like cytokine; sTL1A, soluble TL1A; mTL1A, membrane-bound TL1A; DR3, death domain receptor 3; IL-1ra, IL-1 receptor antagonist; PMX, polymyxin B sulfate; RF+/RA, RF-seropositive RA patients; RF–/RA, RF-seronegative RA patients; OA, osteoarthritis; PEG, polyethylene glycol; CHX, cycloheximide.
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