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*Research Center and
Nephrology Service, Centre hospitalier de l’Université de Montréal, Notre-Dame Hospital, Montreal, Quebec, Canada;
Human Genome Sciences, Rockville, MD 20850; and
Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China
TNF-like ligand 1A (TL1A), a member of the TNF superfamily, is the ligand of DR3 and DcR3. Several types of cells, such as endothelial cells, monocytes/macrophages, dendritic cells, and CD4 and CD8 T cells, are capable of producing this cytokine. In present study, we demonstrated that TL1A aggravated collagen-induced arthritis in mice. It increased collagen-induced arthritis penetrance and clinical scores as well as the severity of the pathological findings. TL1A administration led to the occurrence of multiple enlarged germinal centers in the spleen, and it boosted serum anti-collagen Ab titers in vivo. In vitro, TL1A augmented TNF-
production by T cells upon TCR ligation, and it greatly enhanced Th17 differentiation and IL-17 production. We further showed that human rheumatoid arthritis (RA) synovial fluids had elevated TL1A titers, and human chrondrocytes and synovial fibroblasts were capable of secreting TL1A upon TNF- or IL-1β stimulation. Taken together, these data suggest that TL1A secretion in lymphoid organs might contribute to RA initiation by promoting autoantibody production, and TL1A secretion stimulated by inflammatory cytokines in RA joints might be a part of a vicious circle that aggravates RA pathogenesis.
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 from the Canadian Institutes of Health Research (CIHR) to H.L. (MOP79565 and IMH 79565). It was also supported by grants from the CIHR (MOP57697, MOP69089, and PPP85159), the Kidney Foundation of Canada, the Heart and Stroke Foundation of Quebec, the Quebec Ministry of Economic Development, Innovation and Exportation (PSR-SIIRI-069), and the J.-Louis Levesque Foundation to J.W. It was supported in addition by a group grant from Fonds de la Recherche en Santé du Québec for Transfusional and Hemovigilance Medical Research to J.W.
2 J.Z. and X.W. contributed equally to this work.
3 Current address: Department of Inflammation/Immunology, Pfizer, Inc., 700 Chesterfield Parkway West, Chesterfield, MO 63017.
4 Address correspondence and reprint requests to Dr. Jun Zhang, Department of Inflammation/Immunology, Pfizer, 700 Chesterfield Parkway West, Chesterfield, MO 63017. E-mail address: jun.zhang{at}pfizer.com; or Dr. Hongyu Luo, Laboratory of Immunology, Research Centre, Centre Hospitalier de l’Université de Montréal, Notre-Dame Hospital, Pavillion DeSève, Room Y-5612, 1560 Sherbrooke Street East, Montreal, Quebec H2L 4M1, Canada. E-mail address: hongyu.luo{at}umontreal.ca
5 Abbreviations used in this paper: RA, rheumatoid arthritis; BTIIC, bovine type II collagen; CIA, collagen-induced arthritis; OA, osteoarthritis; RT-qPCR, reverse transcription-quantitative PCR; SF, synovial fibroblast; TL1A, TNF-like ligand 1A.
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