Kim Eugene Y, Moudgil Kamal D
Department of Pharmaceutical Sciences, School of Pharmacy, Washington State University, Spokane, WA, USA.
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Division of Rheumatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Cytokine. 2017 Oct;98:87-96. doi: 10.1016/j.cyto.2017.04.012. Epub 2017 Apr 25.
Pro-inflammatory cytokines promote autoimmune inflammation and tissue damage, while anti-inflammatory cytokines help resolve inflammation and facilitate tissue repair. Over the past few decades, this general feature of cytokine-mediated events has offered a broad framework to comprehend the pathogenesis of autoimmune and other immune-mediated diseases, and to successfully develop therapeutic approaches for diseases such as rheumatoid arthritis (RA). Anti-tumor necrosis factor-α (TNF-α) therapy is a testimony in support of this endeavor. However, many patients with RA fail to respond to this or other biologics, and some patients may suffer unexpected aggravation of arthritic inflammation or other autoimmune effects. These observations combined with rapid advancements in immunology in regard to newer cytokines and T cell subsets have enforced a re-evaluation of the perceived pathogenic attribute of the pro-inflammatory cytokines. Studies conducted by others and us in experimental models of arthritis involving direct administration of IFN-γ or TNF-α; in vivo neutralization of the cytokine; the use of animals deficient in the cytokine or its receptor; and the impact of the cytokine or anti-cytokine therapy on defined T cell subsets have revealed paradoxical anti-inflammatory and immunoregulatory attributes of these two cytokines. Similar studies in other models of autoimmunity as well as limited studies in arthritis patients have also unveiled the disease-protective effects of these pro-inflammatory cytokines. A major mechanism in this regard is the altered balance between the pathogenic T helper 17 (Th17) and protective T regulatory (Treg) cells in favor of the latter. However, it is essential to consider that this aspect of the pro-inflammatory cytokines is context-dependent such that the dose and timing of intervention, the experimental model of the disease under study, and the differences in individual responsiveness can influence the final outcomes. Nevertheless, the realization that pro-inflammatory cytokines can also be immunoregulatory offers a new perspective in fully understanding the pathogenesis of autoimmune diseases and in designing better therapies for controlling them.
促炎细胞因子促进自身免疫炎症和组织损伤，而抗炎细胞因子有助于炎症消退并促进组织修复。在过去几十年中，细胞因子介导事件的这一普遍特征为理解自身免疫性疾病和其他免疫介导疾病的发病机制，以及成功开发类风湿关节炎（RA）等疾病的治疗方法提供了一个广泛的框架。抗肿瘤坏死因子-α（TNF-α）疗法就是这一努力的证明。然而，许多RA患者对这种或其他生物制剂没有反应，一些患者可能会出现关节炎炎症意外加重或其他自身免疫效应。这些观察结果，再加上免疫学在新型细胞因子和T细胞亚群方面的迅速进展，促使人们重新评估促炎细胞因子的致病属性。我们和其他人在关节炎实验模型中进行的研究，包括直接给予干扰素-γ或TNF-α；细胞因子的体内中和；使用缺乏细胞因子或其受体的动物；以及细胞因子或抗细胞因子疗法对特定T细胞亚群的影响，揭示了这两种细胞因子具有矛盾的抗炎和免疫调节属性。在其他自身免疫模型中的类似研究以及在关节炎患者中的有限研究也揭示了这些促炎细胞因子的疾病保护作用。这方面的一个主要机制是致病性辅助性T细胞17（Th17）和保护性调节性T（Treg）细胞之间的平衡发生改变，有利于后者。然而，必须考虑到促炎细胞因子的这一方面是依赖于背景的，因此干预的剂量和时机、所研究疾病的实验模型以及个体反应性的差异都会影响最终结果。尽管如此，认识到促炎细胞因子也可以具有免疫调节作用，为全面理解自身免疫性疾病的发病机制以及设计更好的控制疗法提供了一个新的视角。
