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

点击翻译按钮获取中文摘要

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.