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

血红素加氧酶（HO）将原血红素IX分解为一氧化碳（CO）、游离二价铁（Fe^<2+>）和胆汁素-IXα （bihrum -IXα的前体）。血红素加氧酶(HO)-1， HO的应激诱导同工酶的诱导，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作用：CO作为内源性血管扩张剂维持微血管通畅，而胆红素ixα作为自由基清除剂改善细胞和组织的氧化影响。考虑到HO-1是一种胁迫诱导蛋白，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蛋白的这种未确定的产品非依赖性作用，我们利用人单细胞白血病细胞系U937建立了HO-1野生型和H25A突变体cDNA的稳定转染物，并利用DNA芯片技术进行了人11K转录组分析。计算机数据和蛋白质水平的数据显示，CD11a/CD18（一种调节白细胞募集和抗原呈递的粘附分子）在野生型转染中明显下调，而在突变细胞中没有下调，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。

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.