Development and progression of prostate cancer (PCa) are associated with chronic 
inflammation. The cytokine interleukin 6 (IL6) can influence progression, 
differentiation, survival, and angiogenesis of PCa. To identify novel pathways 
that are triggered by IL6, we performed a gene expression profiling of two PCa 
cell lines, LNCaP and MDA PCa 2b, treated with 5 ng/ml IL6. Interferon (IFN) 
regulatory factor 9 (IRF9) was identified as one of the most prevalent 
IL6-regulated genes in both cell lines. IRF9 is a mediator of type I IFN 
signaling and acts together with STAT1 and 2 to activate transcription of 
IFN-responsive genes. The IL6 regulation of IRF9 was confirmed at mRNA and 
protein levels by quantitative real-time PCR and western blot respectively in 
both cell lines and could be blocked by the anti-IL6 antibody Siltuximab. Three 
PCa cell lines, PC3, Du-145, and LNCaP-IL6+, with an autocrine IL6 loop 
displayed high expression of IRF9. A tissue microarray with 36 PCa tissues 
showed that IRF9 protein expression is moderately elevated in malignant areas 
and positively correlates with the tissue expression of IL6. Downregulation and 
overexpression of IRF9 provided evidence for an IFN-independent role of IRF9 in 
cellular proliferation of different PCa cell lines. Furthermore, expression of 
IRF9 was essential to mediate the antiproliferative effects of IFNα2. We 
concluded that IL6 is an inducer of IRF9 expression in PCa and a sensitizer for 
the antiproliferative effects of IFNα2.