Rabinovitch A
Department of Medicine, University of Alberta, Edmonton, Canada.
Diabetes Metab Rev. 1998 Jun;14(2):129-51. doi: 10.1002/(sici)1099-0895(199806)14:2<129::aid-dmr208>3.0.co;2-v.
Correlation studies between cytokines expressed in islets and autoimmune diabetes development in NOD mice and BB rats have demonstrated that beta-cell destructive insulitis is associated with increased expression of proinflammatory cytokines (IL-1, TNF alpha, and IFN alpha) and type 1 cytokines (IFN gamma, TNF beta, IL-2 and IL-12), whereas non-destructive (benign) insulitis is associated with increased expression of type 2 cytokines (IL-4 and IL-10) and the type 3 cytokine (TGF beta). Cytokines (IL-1, TNF alpha, TNF beta and IFN gamma) may be directly cytotoxic to beta-cells by inducing nitric oxide and oxygen free radicals in the beta-cells. In addition, cytokines may sensitize beta-cells to T-cell-mediated cytotoxicity in vivo by upregulating MHC class I expression on the beta-cells (an action of IFN gamma), and inducing Fas (CD95) expression on beta-cells (actions of IL-1, and possibly TNF alpha and IFN gamma). Transgenic expression of cytokines in beta-cells of non-diabetes-prone mice and NOD mice has suggested pathogenic roles for IFN alpha, IFN gamma, IL-2 and IL-10 in insulin-dependent diabetes mellitus (IDDM) development, and protective roles for IL-4, IL-6 and TNF alpha. Systemic administrations of a wide variety of cytokines can prevent IDDM development in NOD mice and/or BB rats; however, a given cytokine may retard or accelerate IDDM development, depending on the dose and frequency of administration, and the age and the diabetes-prone animal model studied (NOD mouse or BB rat). Islet-reactive CD4+ T-cell lines and clones that adoptively transfer IDDM into young NOD mice have a Th1 phenotype (IFN gamma-producing), but other islet-specific Th1 clones that produce TGF beta can adoptively transfer protection against IDDM in NOD mice. NOD mice with targeted deletions of IL-12 and IFN gamma genes still develop IDDM, albeit delayed and slightly less often. In contrast, post-natal deletions of IL-12 and IFN gamma, also IL-1, TNF alpha, IL-2, and IL-6--by systemic administrations of neutralizing antibodies, soluble receptors and receptor antagonists, and receptor-targeted cytotoxic drugs--significantly decrease IDDM incidence in NOD mice and/or BB rats. These cytokine deletion studies have provided the best evidence for pathologic roles for proinflammatory cytokines (IL-1, TNF alpha, and IL-6) and type 1 cytokines (IFN gamma, IL-2 and IL-12) in IDDM development.
对非肥胖型糖尿病（NOD）小鼠和BB大鼠胰岛中表达的细胞因子与自身免疫性糖尿病发展之间的相关性研究表明，β细胞破坏性胰岛炎与促炎细胞因子（IL-1、TNFα和IFNα）及1型细胞因子（IFNγ、TNFβ、IL-2和IL-12）表达增加有关，而非破坏性（良性）胰岛炎与2型细胞因子（IL-4和IL-10）及3型细胞因子（TGFβ）表达增加有关。细胞因子（IL-1、TNFα、TNFβ和IFNγ）可通过在β细胞中诱导一氧化氮和氧自由基而直接对β细胞产生细胞毒性。此外，细胞因子可通过上调β细胞上的MHC I类分子表达（IFNγ的作用）以及诱导β细胞上Fas（CD95）表达（IL-1的作用，可能还有TNFα和IFNγ的作用），使β细胞在体内对T细胞介导的细胞毒性敏感。在非糖尿病易患小鼠和NOD小鼠的β细胞中细胞因子的转基因表达提示IFNα、IFNγ、IL-2和IL-10在胰岛素依赖型糖尿病（IDDM）发展中起致病作用，而IL-4、IL-6和TNFα起保护作用。全身性给予多种细胞因子可预防NOD小鼠和/或BB大鼠发生IDDM；然而，根据给药剂量和频率以及所研究的年龄和糖尿病易患动物模型（NOD小鼠或BB大鼠），某一特定细胞因子可能延缓或加速IDDM的发展。能将IDDM过继转移给年轻NOD小鼠的胰岛反应性CD4+T细胞系和克隆具有Th1表型（产生IFNγ），但其他产生TGFβ的胰岛特异性Th1克隆可过继转移对NOD小鼠IDDM的保护作用。IL-12和IFNγ基因靶向缺失的NOD小鼠仍会发生IDDM，尽管有所延迟且发生率略低。相反，通过全身性给予中和抗体、可溶性受体和受体拮抗剂以及受体靶向细胞毒性药物，在出生后缺失IL-12和IFNγ，以及IL-1、TNFα、IL-2和IL-6，可显著降低NOD小鼠和/或BB大鼠的IDDM发生率。这些细胞因子缺失研究为促炎细胞因子（IL-1、TNFα和IL-6）及1型细胞因子（IFNγ、IL-2和IL-12）在IDDM发展中的病理作用提供了最佳证据。
