Zhang Jun, Wang Xuehai, Fahmi Hassan, Wojcik Susan, Fikes James, Yu Youhua, Wu Jiangping, Luo Hongyu
Research Center, Entre Hospitalier de l'Université de Montréal, Notre-Dame Hospital, Montreal, Quebec, Canada.
J Immunol. 2009 Oct 15;183(8):5350-7. doi: 10.4049/jimmunol.0802645. Epub 2009 Sep 28.
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-alpha 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-alpha or IL-1beta 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.
肿瘤坏死因子样配体1A（TL1A）是肿瘤坏死因子超家族的成员，是DR3和DcR3的配体。几种类型的细胞，如内皮细胞、单核细胞/巨噬细胞、树突状细胞以及CD4和CD8 T细胞，都能够产生这种细胞因子。在本研究中，我们证明TL1A会加重小鼠胶原诱导的关节炎。它增加了胶原诱导的关节炎发病率和临床评分以及病理结果的严重程度。给予TL1A导致脾脏中出现多个肿大的生发中心，并在体内提高血清抗胶原抗体滴度。在体外，TL1A在TCR连接后增强T细胞产生肿瘤坏死因子-α，并且极大地增强Th17分化和白细胞介素-17的产生。我们进一步表明，人类类风湿性关节炎（RA）滑液中TL1A滴度升高，并且人类软骨细胞和滑膜成纤维细胞在肿瘤坏死因子-α或白细胞介素-1β刺激下能够分泌TL1A。综上所述，这些数据表明淋巴器官中TL1A的分泌可能通过促进自身抗体产生而有助于类风湿性关节炎的起始，并且类风湿性关节炎关节中炎性细胞因子刺激的TL1A分泌可能是加重类风湿性关节炎发病机制的恶性循环的一部分。
