Clark Ian A
School of Biochemistry and Molecular Biology, Australian National University, Canberra, ACT, Australia.
Cytokine Growth Factor Rev. 2007 Jun-Aug;18(3-4):335-43. doi: 10.1016/j.cytogfr.2007.04.002. Epub 2007 May 9.
This review summarizes the origins of the insight that excess production of pro-inflammatory cytokines caused a constellation of changes that contribute to pathophysiology of disease. This connection was made following the original 1975 TNF (tumor necrosis factor) publication from New York describing how activated macrophages kill tumors. The study caught the eye of a group in London who were trying to understand how the same in vivo macrophage activation would protect mice against the erythrocytic protozoan parasites that cause malaria and babesiosis. Based on collaborative research between these two groups, it was argued in 1981 that TNF and related cytokines initiated events that caused pathology, as well as parasite death within red cells in these infectious diseases. This proved to be a key conceptual advance. It was also argued that the pathology of bacterial sepsis logically had TNF origins. Once TNF was cloned in 1985, allowing its specific analysis in serum and neutralization in vivo, the involvement of this cytokine in infectious disease pathology was pursued by a number of groups. Some researchers found that once "their" cytokine was cloned and sequenced, they had been unwittingly expanding knowledge on TNF for several years. By the late 1980s excess TNF production was proposed to be central to acute systemic viral diseases. This family of cytokines is now at the centre of investigations to understand the mechanisms of acute systemic viral diseases, including influenza and the hemorrhagic viral diseases. With its implication as the master regulator of other inflammatory cytokines in the synovial membrane, TNF has also become the major cytokine in the pathogenesis of chronic inflammatory disease. Its neutralization has proven to be a potent treatment for rheumatoid arthritis and Crohn's disease.
促炎细胞因子的过度产生会引发一系列变化，这些变化导致了疾病的病理生理学过程。这种联系是在1975年纽约首次发表关于肿瘤坏死因子（TNF）的文章之后建立的，该文章描述了活化的巨噬细胞如何杀死肿瘤。这项研究引起了伦敦一个研究小组的关注，他们试图了解体内相同的巨噬细胞激活如何保护小鼠免受导致疟疾和巴贝斯虫病的红细胞原生动物寄生虫的侵害。基于这两个小组的合作研究，1981年有人提出，TNF和相关细胞因子引发了导致病理变化的事件，以及这些传染病中红细胞内寄生虫的死亡。这被证明是一个关键的概念性进展。还有人认为，细菌性败血症的病理逻辑上源于TNF。1985年TNF被克隆后，使得能够在血清中对其进行特异性分析并在体内进行中和，许多研究小组开始研究这种细胞因子在传染病病理中的作用。一些研究人员发现，一旦“他们的”细胞因子被克隆和测序，他们不知不觉中已经在TNF方面积累了数年的知识。到20世纪80年代末，有人提出TNF的过度产生是急性全身性病毒疾病的核心。现在，这个细胞因子家族是理解急性全身性病毒疾病（包括流感和出血性病毒疾病）机制的研究核心。由于TNF被认为是滑膜中其他炎症细胞因子的主要调节因子，它也已成为慢性炎症性疾病发病机制中的主要细胞因子。事实证明，中和TNF是治疗类风湿性关节炎和克罗恩病的有效方法。
