Distal Promoter Regions Are Responsible for Differential Regulation of Human Orosomucoid-1 and -2 Gene Expression and Acute Phase Responses

Abstract

Human orosomucoid (ORM) is a major acute-phase plasma protein, encoded by 2 highly homologous genes, ORM1 and ORM2. Human ORM induction is assumed to be regulated by each proximal promoter region, where putative glucocorticoid responsive elements and CCAAT/enhancer binding protein (C/EBP)β binding sites are located. However, the details of the differential regulation of these genes remain unknown. To explore this, we assessed the role of the distal promoter region of each ORM in HeLa cells. Luciferasereporter activities of full constructs, containing approximately 1.1 kbp (FULL), and those of deletion constructs, containing up to 188 bp region (DEL) upstream of the transcription start sites of ORM1 and ORM2 were compared under both basal and inducer-treated conditions. For ORM1 and ORM2 DEL constructs, significantly increased activities after dexamethasone (DEX) treatments (alone and combined with interleukin (IL)-1β) were observed. Significantly higher FULL construct activities than DEL construct activities were observed for ORM1 after IL-1β treatment, while those for ORM2 were significantly lower at basal level and after DEX treatments. Upon C/EBPβ overexpression, FULL construct activities were significantly higher than those of DEL constructs at basal level and after IL-1β treatment for ORM1, and at basal level and after inducer-treatments for ORM2. Higher transcription-induction activity in the distal promoter region was evident for ORM1 in the absence of C/EBPβ overexpression, and for ORM2 under C/EBPβ overexpression conditions. These findings suggest that the ORM distal promoter region differentially regulates expression of ORM genes at basal level and in acute phase responses.Key words orosomucoid; alpha 1 acid glycoprotein; distal promoter region; acute phase response; gene regulation Human orosomucoid (ORM), also known as alpha-1-acid glycoprotein, is an approximately 40-kDa acute-phase plasma protein. It has anti-inflammatory and immunomodulatory properties, and has effects on drug responses due to its drugbinding properties. 1-3)Human ORM is encoded by 2 genes, ORM1 and ORM2, with sequence homology across the coding region and the proximal promoter region (approximately 800-bp upstream from the transcription initiation site) of 94% and 98%, respectively.1-4) Despite this high homology, gene expressions of ORM1 and ORM2 are known to be differentially regulated. ORM1 is preferentially transcribed in human liver, a human hepatoma cell line and in transgenic mice carrying human ORM genes, 4,5) which may related to higher plasma concentration of ORM1 in human subjects.6-10) Both ORMs are increased in the patients with cancers, burnt injury or surgical operation, but their induction pattern varies according to pathophysiological conditions. [6][7][8][9][10] This may indicate that gene expression of ORM1 and ORM2 is differentially regulated; however, this possibility has not yet been evaluated. In the proximal promoter region of rodent orm, it is identified a glucocorticoid (GC) responsive element (GRE) and ...

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