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HEME OXYGENASE-1-MEDIATED STRESS RESPONSE OF LIVER AND RETICULOENDOTHELIAL SYSTEM

血红素加氧酶-1介导的肝脏和网状内皮系统应激反应

基本信息

批准号：
12470128
负责人：
SUEMATSU Makoto
金额：
$ 4.29万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

Heme oxygenase (HO) degrades protoheme IX by cleaving its a-methene bridge into carbon monoxide (CO), free divalent iron (Fe^<2+>) and biliverdin-IXα, the precursor of bihrubm-IXα. An induction of heme oxygenase (HO)-1, the stress-inducible isozyme of HO, has been shown to attenuate inflammatory responses and post-transplantation tissue injury. Mechanisms for the HO-1-mediated alterations in cell and organ functions involve biological actions of the reaction products: CO serves as an endogenous vasodilator to maintain microyascular patency, while bilirubin-IXα accounts for a radical scavenger that ameliorates oxidative impacts on cells and tissues. Considering that HO-1 is a stress- inducible protein, it is not unreasonable to hypothesize that the protein per se could exert its biological effects on cells, independently of its catalytic activities. In order to explore such unidentified product-independent actions of the HO-1 protein, we established stable transfectants of wild-type HO-1 and H25A mutant cDNA using human monoblastic leukemia cell line U937, and carried out human 11K transcriptome analyses by DNA chip technology. The data in-silico together with those at protein levels revealed that CD11a/CD18, an adhesion molecule that regulates leukocyte recruitment and antigen presentation, was markedly down-regulated in the wild-type transfectants but not in the mutant cells, while lysosomal enzymes such as proteinase 3 increased in both wild-type and mutant cells. These results suggest that HO-1 induction could alter function of inflammatory cells through product-dependent and -independent mechanisms.

血红素加氧酶（HO）通过将血红素IX的α-亚甲基桥断裂成一氧化碳（CO）、游离二价铁（Fe^2+）和胆绿素IX α（bihrubm-IXα的前体）来降解血红素IX。血红素氧合酶（HO）-1，应激诱导型HO同工酶的诱导，已被证明可以减轻炎症反应和移植后组织损伤。HO-1介导的细胞和器官功能改变的机制涉及反应产物的生物学作用：CO作为内源性血管扩张剂维持微血管通畅，而玉红蛋白-IX α作为自由基清除剂改善氧化对细胞和组织的影响。考虑到HO-1是一种应激诱导蛋白，假设该蛋白本身可以独立于其催化活性而对细胞发挥其生物学作用并非不合理。为了探索HO-1蛋白的这种未知的产物非依赖性作用，我们利用人单核细胞白血病细胞系U937建立了野生型HO-1和H25 A突变体cDNA的稳定转染细胞，并通过DNA芯片技术进行了人11 K转录组分析。计算机数据与蛋白质水平的数据一起显示，CD 11 a/CD 18（一种调节白细胞募集和抗原呈递的粘附分子）在野生型转染子中显著下调，但在突变细胞中未下调，而溶酶体酶（如蛋白酶3）在野生型和突变细胞中均增加。这些结果表明，HO-1诱导可以通过产物依赖性和非依赖性机制改变炎症细胞的功能。