Abstract Cancer-related inflammation (CRI) can promote or inhibit tumor development, growth and progression. A key role in CRI may be the infiltration of immune cells. During the inflammation process immune cells are recruited to the tumor. They produce cytokines and inflammatory molecules like reactive oxygen and nitrogen species. However, in prostate Cancer (PCa) the role of inflammation is not well understood. Meta-analysis conducted on case-control studies showed an association of prostatitis and the risk of prostate cancer. Moreover, clinical data showed that several cytokines e.g. interleukin (IL)-6, IL-8 and IL-4 are significantly elevated in sera of patients with CRPC. In this study we investigated the role of short-term and long-term IL-4 treatment on the castration resistant prostate cancer lines PC3, Du145 and LNCaP-IL6+. For short-term treatment conditions cells were incubated with increasing concentrations of IL-4 (0.1-10 ng/ml) for 96 h in full growth medium. Neither proliferation rate nor cell-viability of the three cell lines were changed under these conditions. On the other hand, from the known IL-4 downstream targets only phosphorylation of STAT6 was readily detectable after IL-4 treatment, whereas phosphorylation status of the MAP kinases ERK1/2 and AKT was not affected. Among the STAT6 regulated genes only SOCS-1 was upregulated after IL-4 treatment. For long-term treatment conditions PC3, Du145 and LNCaP-IL-6+ cell lines were treated with 5 ng/ml IL-4 over a period of 30 passages. Interestingly, a morphologic change of the PC3 cell line to a more dedifferentiated phenotype was observable after 10 passages of IL-4 treatment and peaked after 20 passages with 30-50% of all cells showing this morphology. In order to evaluate possible effects of IL-4 on stem-cell like phenotype, we analyzed the IL-4 treated PC3 cell line for the presence of stem cell markers CD44, CD133 and integrin α2 by FACS. Indeed, high expression of CD44 and integrin α2 was observable in a subpopulation of PC3 cells. Expression of CD133 was negative due to hypermethylation of the gene. The percentage of marker-positive cells was increasing with passage, showing that IL-4 long-term treatment might be favorable for cells with cancer stem cell-like properties. Collectively, our results show that IL-4 long-term treatment might promote cells with stem cell-like characteristics and therefore influence the progression of the cancerous disease. This work was funded by the European Union FP7 Marie Curie Initial Training Network PRO-NEST. 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 3350. doi:1538-7445.AM2012-3350