Towards cytokine insight in sight.
Towards cytokine insight in sight.
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对细胞因子的洞察就在眼前。
DOI：
10.1136/bjo.79.11.970
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发表时间：
1995
期刊：
影响因子：
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通讯作者：
Rosenbaum,JT
中科院分区：
文献类型：
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作者：
Rosenbaum,JT
在最近发表在《柳叶刀》上的一篇论文中，“中和细胞因子肿瘤坏死因子a（TNF-α）的抗体被报道在免疫介导的疾病类风湿性关节炎中产生明显的和稍微持续的症状缓解。本报告希望细胞因子的中和作用最终可能对炎症性眼病具有治疗价值，包括葡萄膜炎、角膜炎、巩膜炎、角膜移植排斥、囊样黄斑水肿，以及可能的纤维化或血管生成性疾病，包括糖尿病性视网膜病变、增殖性玻璃体视网膜病变、黄斑变性、翼状胬肉和降低眼内压手术后的纤维化。为了考虑细胞因子抑制的挑战和潜力，有必要回顾有关细胞因子和细胞因子功能的几个原则。细胞因子是细胞用于通信的蛋白质。免疫系统中的细胞广泛利用细胞因子。细胞因子包括至少15种白细胞介素、肿瘤坏死因子、趋化因子、集落刺激因子、干扰素和多种生长因子如转化生长因子1B（TGF-β）的扩展家族。脂质、一氧化氮和肽通常不被认为是细胞因子，尽管这些物质也参与细胞通讯。靶向细胞因子的原理很简单。细胞因子对于免疫系统的功能是必不可少的。许多疾病是由病理性免疫反应引起的。因此，中断细胞因子的通讯将导致炎症减少。此外，包括白细胞介素-I（IL-1）、TNF-α、IL-6、IL-8、IL-2和粒细胞巨噬细胞集落刺激因子的多种细胞因子可以直接注射到眼睛中，导致显著的炎症。2另一方面，直接注射IL-10或TGF-1可能具有抗炎作用。关于细胞因子功能的几个基本原则可以帮助我们理解干扰细胞因子控制的挑战的复杂性。首先，细胞因子是多效性的。这意味着它们可以靶向和调节许多基因。例如，在其他功能中，IL-1刺激成纤维细胞生长，增加胶原合成，引起骨吸收，对某些肿瘤细胞具有细胞毒性，对淋巴细胞具有趋化性，刺激前列腺素合成，引起嗜碱性粒细胞组胺释放，诱导发热，并刺激其他细胞因子的合成。其次，细胞因子通常共享功能，也就是说，它们是多余的。例如，IL-1和TNF都可以激活淋巴细胞，作为热原，引起肌肉恶病质，诱导急性期蛋白合成，激活内皮细胞，引起成纤维细胞增殖，诱导肿瘤坏死。因此，单个细胞因子的拮抗作用可能改变许多下游效应。例如，血管内皮生长因子（VEGF）最近被认为是血管生成疾病如糖尿病视网膜病变的主要促成因素。3.VEGF在某些细胞中可被IL-1调节。第四，大多数细胞因子的作用是局部的而不是全身的。一般来说，细胞因子不像内分泌激素那样作用于远端部位。细胞因子可以
In a recent paper in the Lancet,'antibodies that neutralise the cytokine, tumour necrosis factor a (TNF-a), were reported to produce marked and somewhat sustained relief of symptoms in the immune mediated disease rheumatoid arthritis. This report lends hope that the neutralisation of cytokines may eventually be of therapeutic value in inflammatory eye diseases including uveitis, keratitis, scleritis, comeal transplant rejection, cystoid macular oedema, and possibly fibrotic or angiogenic diseases including diabetic retinopathy, proliferative vitreoretinopathy, macular degeneration, pterygium, and fibrosis after surgery to reduce intraocular pressure. In order to consider the challenges and potential of cytokine inhibition, it is necessary to review several principles about cytokines and cytokine function. Cytokines are proteins that cells use for communication. The cells in the immune system utilise cytokines extensively. The cytokines include an expanding family of at least 15 interleukins, the tumour necrosis factors, chemokines, colony stimulating factors, interferons, and a variety of growth factors such as transforming growth factor 1B (TGF-P). Lipids, nitric oxide, and peptides are usually not considered cytokines although these substances, too, are involved in cellular communication. The rationale to target cytokines is simple. Cytokines are essential for the function of the immune system. Many diseases result from a pathological immune response. Therefore, interruptingthe cytokine communication will result in diminished inflammation. Furthermore, a variety of cytokines including interleukin-1 (IL-1), TNF-a, IL-6, IL-8, IL-2, and granulocyte macrophage colony stimulating factor can be directly injected into the eye with significant inflammation resulting. 2 On the other hand the direct injection of IL-10 or TGF-1 may be anti-inflammatory. Several basic principles with regard to cytokine function may help us to understand the complexity of the challenge in interfering with cytokine control. First of all cytokines are pleiotropic. This means that they have may targets and regulate many genes. For example, among other functions, IL-1 stimulates fibroblast growth, increases collagen syn-thesis, causes bone resorption, is cytotoxic for some tumour cells, is chemotactic for lymphocytes, stimulates prostaglandin synthesis, causes basophil histamine release, induces fever, and stimulates synthesis of other cytokines. Secondly, cytokines often share functions-that is, they are redundant. For example, both IL-1 and TNF can activate lymphocytes, act as pyrogens, cause muscle cachexia, inducethe acute phase protein synthesis, activate endothelial cells, cause fibroblast proliferation, and induce tumour necrosis.Thirdly, cytokines function within a network. Conse-quently the antagonism ofa single cytokine may alter many downstream effects. For example, vascular endothelial growth factor (VEGF) has recently been implicated as a major contributor to angiogenic disease such as diabetic retinopathy. 3 VEGF can be regulated in some cells byIL-1. Fourthly, most effects of cytokines are local rather than systemic. In general, cytokines are not intended to act at a distant site as would an endocrine hormone. Cytokines can