权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Multiple organ dysfunction caused by cytokines, IL-12 and IL-18.-damages in the gland-

细胞因子、IL-12 和 IL-18 引起的多器官功能障碍。-腺体损伤-

基本信息

批准号：
11470045
负责人：
OKAMURA Haruki
金额：
$ 4.42万
依托单位：
Hyogo College of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470045/
关键词：
Nitric oxide Interleukin18 Interleukin12 Lacrimal gland 多臓器障害 IL-12 IL-18 活性酸素腺組織アポトーシス

项目摘要

IL-18 was discovered in 1995 as an IFN-γ-inducing factor in this institute. It is a cytokine with pleiotropic actions and now under vigorous investigation. IL-18 induces iNOS, COX-2, Fas ligand, and not only Th1 cytokines IFN-γ but Th2 cytokine such as IL-4, IL-5, and IL-13. The actions of IL-18 was reviewed by us in Ann.Rev.Immunol. (Annu.Rev.Immunol. 2001, 19 ; 423-474). IL-18 is profoundly involved in inflammatory reactions. And in the present study, we have shown that IL-18 in combination with IL-12 causes multiple organ dysfunction when administered to mice. When IL-12 and IL-18 were separately given to mice, they caused apparently no pathological changes, but when given in combination, they caused severe erosion in the intestine, atrophy in the thymus, fatty degeneration in the liver, and death in a few days. These cytokines failed to cause these pathological changes in IFN-γ-deficient mice, and induced milder changes in iNOS deficient mice. The change first appeared in the gland tissues and mumerous apoptotic cells were observed in the lacrimal gland. The administration of IL-12 and IL-18 failed to cause apoptotic changes in iNOS deficient mice. Various caspase inhibitors diminished the histological changes in the lacrimal gland. Thus, it was shown that IL-18 together with IL-12 is involved in the tissue damage through strong induction of IFN-γ. Moreover the down stream product, nitric oxide and reactive oxygen species were suggested to be directly responsible for the tissue damages. Thus IL-18 and IL-12 activate the destructive pathway by inducing IFN-γ, but recent studies revealed that IL-18 induces Th2 or anti-inflammatory cytokines such as IL-4, IL-5, and IL-13 in the absence of IL-12. Therefore, IL-18 may be involved also in the regulation of destructive pathway by inhibiting Th1 cytokines through induction of Th2 cytokines. Much remains to be clarified for this attractive cytokine.

IL-18是1995年本所发现的一种IFN-γ诱导因子。它是一种具有多效性作用的细胞因子，目前正在进行积极的研究。IL-18诱导iNOS、考克斯-2、Fas配体，并且不仅诱导Th 1细胞因子IFN-γ，还诱导Th 2细胞因子如IL-4、IL-5和IL-13。我们在Ann.Rev.Immunol.（Annu.Rev.Immunol.2001，19 ; 423-474）中综述了IL-18的作用。IL-18与炎症反应密切相关。在目前的研究中，我们已经表明，IL-18与IL-12联合给药小鼠时会导致多器官功能障碍。当IL-12和IL-18分别给予小鼠时，它们显然没有引起病理变化，但当它们联合给予时，它们引起肠道严重糜烂，胸腺萎缩，肝脏脂肪变性，并在几天内死亡。这些细胞因子未能在IFN-γ缺陷小鼠中引起这些病理变化，而在iNOS缺陷小鼠中引起较温和的变化。泪腺组织首先发生变化，泪腺内可见大量凋亡细胞。IL-12和IL-18的给药未能引起iNOS缺陷小鼠的凋亡变化。各种半胱天冬酶抑制剂减轻泪腺的组织学变化。因此，表明IL-18与IL-12一起通过IFN-γ的强诱导参与组织损伤。此外，下游产物一氧化氮和活性氧被认为是组织损伤的直接原因。因此，IL-18和IL-12通过诱导IFN-γ激活破坏性途径，但最近的研究表明，在不存在IL-12的情况下，IL-18诱导Th 2或抗炎细胞因子，如IL-4、IL-5和IL-13。因此，IL-18也可能通过诱导Th 2细胞因子抑制Th 1细胞因子参与破坏性途径的调节。对于这种有吸引力的细胞因子，仍有许多问题有待澄清。