Department for Molecular Biomedical Research, VIB, Ghent, Belgium.
Cytokine Growth Factor Rev. 2011 Oct-Dec;22(5-6):311-9. doi: 10.1016/j.cytogfr.2011.09.004. Epub 2011 Oct 1.
The TNF signaling pathway is a valuable target in the therapy of autoimmune diseases, and anti-TNF drugs are successfully used to treat diseases such as rheumatoid arthritis, Crohn's disease and psoriasis. By their ability to interfere with inflammatory processes at multiple levels, these TNF blockers have become invaluable tools to inhibit the inflammation induced damage and allow recovery of the affected tissues. Unfortunately this therapy has some drawbacks, including increased risk of infection and malignancy, and remarkably, the onset of new auto-immune diseases. Some of these effects are caused by the unwanted abrogation of beneficial TNF signaling. More specific targeting of the pathological TNF-induced signaling might lead to broader applicability and improved safety. Specificity might be increased by inhibiting the soluble TNF/TNFR1 axis while leaving the often beneficial transmembrane TNF/TNFR2 signaling untouched. This approach looks promising because it inhibits the pathological effects of TNF and reduces the side effects, and it opens the way for the treatment of other diseases in which TNFR2 inhibition is detrimental. In this review we give an overview of in vivo mouse studies of TNF mediated pathologies demonstrating that the blockade or genetic deletion of sTNF or TNFR1 is preferable over total TNF blockade.
TNF 信号通路是治疗自身免疫性疾病的一个有价值的靶点，抗 TNF 药物已成功用于治疗类风湿关节炎、克罗恩病和银屑病等疾病。这些 TNF 阻滞剂通过在多个层面干扰炎症过程，成为抑制炎症诱导损伤和允许受影响组织恢复的宝贵工具。不幸的是，这种治疗存在一些缺点，包括感染和恶性肿瘤风险增加，而且令人惊讶的是，还会出现新的自身免疫性疾病。这些影响中的一些是由于 TNF 信号的有益阻断而引起的。通过抑制可溶性 TNF/TNFR1 轴，同时不影响通常有益的跨膜 TNF/TNFR2 信号，可能会提高靶向治疗的特异性。这种方法看起来很有前途，因为它可以抑制 TNF 的病理性作用，减少副作用，并为治疗其他 TNFR2 抑制有害的疾病开辟了道路。在这篇综述中，我们概述了 TNF 介导的病理学的体内小鼠研究，证明了阻断或遗传缺失可溶性 TNF 或 TNFR1 优于完全阻断 TNF。
