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Regulation of inflammatory response by an inhibitory cytokine in a mode of inhiditory cybemetics

抑制性细胞因子在抑制性控制学模式下调节炎症反应

基本信息

批准号：
05454182
负责人：
YOSHINAGA Masaru
金额：
$ 4.22万
依托单位：
KUMAMOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05454182/
关键词：
INFLAMMATION LEUKOCYTE INFILTRATION TISSURY INJURY IL-lbeta TNFalpha IL-lra NEUTROPHIL THERAPY IL-1 IL-1ra TNFα LPS 白血球滲潤関節炎

项目摘要

We developed rabbit recombinant IL-lbeta and IL-lra, as well as antibodies against these cytokines. Using these materials and anti-rabbit TNFalpha, we investigated the role of IL-l and TNFalpha in the pathogenesis of LPS-arthritis in rabbits. In the LPS-induced arthritis leukocyte infiltration peaked at 9hrs while destruction of caltilagepeaked at 24 hrs of the inflammation. When 10mug of IL-lra was injected simultaneously with LPS,the resulting neutrophil infiltration was inhibited by 70%during a whole observation period until 48 hrs and destruction of caltilage was completely prevented. Anti-TNFalpha (100mug) antibody also inhibited neutrophil infiltration by 70% and completely preveted destruction of caltilage. A combination of these two inhibitory substances produced furher suppression of neutrophil-infiltration by more than 90% and complete abrogation of caltilage-destruction. In the LPS-arthritis, production of IL-l peaked at 6hr and its amount was 196.7 pg/joint and the most of the produced IL-l was beta in form. Production of TNFalpha peaked at 2hr and its amount was 12.5 ng/joints. To investigate the role of neutrophils in the desruction of caltilate, we made neutropenic rabbits using i.v.nitrogen mustard. LPS induced no caltilage destruction and no production of IL-lbeta in the neutropenic rabbits, while production of TNFalpha was unchanges in comparison with non-leukopenic rabbits. Injection of IL-lbeta (187 pg) into the leukopenic rabbits did not result in destruction of caltilage. Thus, both TNFalpha and IL-lbeta is the key mediators for induction of LPS-stimulated arthritis. But, these cytokines are not directly responsible for tissue damage. Next, we investigated a production which may involved in the destruction of caltilage and we found that neutrophil-derived superoxide anion and elastase is responsible for destruction of caltilage in this inflammation.

我们开发了兔重组il - β和IL-lra，以及针对这些细胞因子的抗体。利用这些材料和抗兔TNFalpha，我们研究了il - 1和TNFalpha在兔lps -关节炎发病机制中的作用。在lps诱导的关节炎中，白细胞浸润在炎症发生的第9小时达到峰值，而软骨破坏在炎症发生的第24小时达到峰值。当10mug IL-lra与LPS同时注射时，整个观察期内中性粒细胞的浸润被抑制70%，直至48 h，完全阻止了软骨的破坏。抗tnfalpha （100mug）抗体也能抑制70%的中性粒细胞浸润，完全防止对软骨的破坏。这两种抑制物质的结合进一步抑制了90%以上的中性粒细胞浸润，并完全消除了软骨破坏。在lps -关节炎中，il - 1的产生在6hr时达到峰值，其量为196.7 pg/关节，产生的il - 1大部分以β形式存在。TNFalpha的产生在2hr达到峰值，其量为12.5 ng/关节。为了研究中性粒细胞在骨骼肌破坏中的作用，我们用氮芥灌胃制造了嗜中性粒细胞减少的家兔。在中性粒细胞减少的家兔中，LPS没有引起骨骼肌破坏和il - β的产生，而与非白细胞减少的家兔相比，TNFalpha的产生没有变化。在白细胞减少的家兔体内注射il - β (187pg)，未造成软骨的破坏。因此，tnf - α和il - β都是诱导lps刺激关节炎的关键介质。但是，这些细胞因子并不直接导致组织损伤。接下来，我们研究了一种可能参与软骨破坏的产物，我们发现中性粒细胞衍生的超氧阴离子和弹性蛋白酶在这种炎症中负责软骨的破坏。