Reichwald Kirsten, Jørgensen Tina Z, Tougaard Peter, Skov Søren
Laboratory of Immunology, Faculty of Medical and Health Sciences, University of Copenhagen, Frederiksberg C, Denmark.
PLoS One. 2014 Jan 8;9(1):e85793. doi: 10.1371/journal.pone.0085793. eCollection 2014.
An elevated level of the cytokine TL1A is known to be associated with several autoimmune diseases, e.g. rheumatoid arthritis and inflammatory bowel disease. However, the mode of action of TL1A remains elusive. In this study, we investigated the role of TL1A in a pro-inflammatory setting, using human leukocytes purified from healthy donors. We show that TL1A, together with IL-12, IL-15 and IL-18, directly induces the production of IL-6 and TNF-α from leukocytes. Interestingly, TL1A-induced IL-6 was not produced by CD14⁺ monocytes. We further show that the produced IL-6 is fully functional, as measured by its ability to signal through the IL-6 receptor, and that the induction of IL-6 is independent of TCR stimulation. Furthermore, the transcription factor PLZF was induced in stimulated cells. These results offer a substantial explanation for the role of TL1A, since TNF-α and IL-6 are directly responsible for much of the inflammatory state in many autoimmune diseases. Our study suggests that TL1A is a possible target for the treatment of autoimmune diseases.
已知细胞因子TL1A水平升高与多种自身免疫性疾病相关，如类风湿性关节炎和炎症性肠病。然而，TL1A的作用模式仍不清楚。在本研究中，我们使用从健康供体中纯化的人白细胞，研究了TL1A在促炎环境中的作用。我们发现，TL1A与IL-12、IL-15和IL-18一起，直接诱导白细胞产生IL-6和TNF-α。有趣的是，TL1A诱导产生的IL-6并非由CD14⁺单核细胞产生。我们进一步表明，所产生的IL-6具有完全的功能，这通过其通过IL-6受体发出信号的能力来衡量，并且IL-6的诱导独立于TCR刺激。此外，转录因子PLZF在受刺激的细胞中被诱导。这些结果为TL1A的作用提供了重要解释，因为TNF-α和IL-6直接导致了许多自身免疫性疾病中的大部分炎症状态。我们的研究表明，TL1A可能是治疗自身免疫性疾病的一个靶点。
