Abstract Several studies have demonstrated a significant immunological impact of single nucleotide polymorphisms in Interferon (IFN)-related genes, such as Toll-Like Receptor (TLR)3 and TLR4. We recently reported that patients with the AA-genotype of a SNP in the IFN-alpha8 (IFNA8) promoter region was associated with better overall survival of patients with WHO grade 2 and 3 gliomas compared to patients with the AC-genotype. Based on these observations we hypothesized that the A-allele in the promoter of IFNA8 allows for enhanced transcription factor binding and expression levels of IFNA8 compared with the C-allele. Analyses of THP-1 cells transfected with a luciferase gene downstream of a short sequence containing the SNP in the IFNA8 promoter demonstrated that the A-allele results in enhanced promoter activity. In silico analysis suggested c-Krox and ELK-1 as likely transcription factors that bind to the IFNA8 polymorphic region. Co-transfection of plasmids encoding the c-Krox or ELK-1 and the luciferase constructs revealed that ELK-1 negatively regulated promoter activity with the A but not C-allele, while c-Krox could not affect activity regardless of allele. Consistently, transfection of ELK-1 siRNA into THP-1 cells resulted in increased promoter activity. To further identify factors that contribute to the enhanced A-allele promoter activity we assessed the effect drugs that inhibit intracellular signaling pathways: PD98059 for inhibiting MEK/ERK, SB203580 a p38 inhibitor, and PPase-2B for de-phosphorylating small molecules. Use of any of the inhibitor resulted in decreased activity of the A-allele promoter activity indicating that multiple proteins or a protein common to multiple pathways seems to be involved. Taken together our data demonstrates that the A-allele in the IFNA8 promoter, which is associated with better glioma patient survival, allows for enhances promoter activation which is negatively regulated by ELK-1 and further regulate by multiple signaling pathways. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1246. doi:1538-7445.AM2012-1246