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

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)beta 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. Luciferase-reporter 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 ORM and ORM2 DEL constructs, significantly increased activities after dexamethasone (DEX) treatments (alone and combined with interleukin (IL)-1 beta were observed. Significantly higher FULL construct activities than DEL construct activities were observed for ORM after IL-1 beta treatment, while those for ORM2 were significantly lower at basal level and after DEX treatments. Upon C/EBP beta overexpression, FULL construct activities were significantly higher than those of DEL constructs at basal level and after IL-1 beta treatment for ORM, 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/EBP beta overexpression, and for ORM2 under C/EBP beta 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.