Serum response elements activate and cAMP responsive elements inhibit expression of transcription factor Egr-1 in synovial fibroblasts of rheumatoid arthritis patients

Analyzing the induction kinetics and promoter elements regulating the expre ssion of the transcription factor Egr-1, we found elevated levels of Egr-1- encoding mRNA in synovial fibroblasts of rheumatoid arthritis (RA) patients when compared to controls, By contrast, synovial lymphocytes and macrophag es do not show an elevated Egr-1 transcription. Therefore, the overexpressi on of Egr-1 may serve as a diagnostic marker to characterize synovial fibro blasts of RA patients. To study the regulatory mechanisms controlling Egr-1 expression we analyzed the function of transcription factor binding sites located in the Egr-1 promoter. Individual transcription factor binding site s within the Egr-1 promoter were specifically mutated and Egr-1 promoter ac tivity was tested using reporter gene constructs. Our experiments demonstra te that serum response elements are the main positive regulators and bindin g to a cAMP responsive element represents the major negative regulator for Egr-1 expression in synovial fibroblasts, In addition, we functionally defi ned a new element, which was not yet described in the human Egr-1 promoter and which serves as a second negative regulatory element for Egr-1 expressi on. Therefore increased serum response factor activity or failure of Egr-1 repressing signals may account for Egr-1 overexpression in RA synovial fibr oblasts.