IL-27/IL-27RA signaling may modulate inflammation and progression of benign prostatic hyperplasia via suppressing the LPS/TLR4 pathway

BACKGROUND: Benign prostatic hyperplasia (BPH) is the most common urologic disease affecting aging men. The pathogenesis of BPH is multi-factorial, and chronic inflammation (CI) might be the central mechanism. Interleukin (IL)-27 signaling has been suggested as a modulator in autoimmune and inflammatory conditions. In this study, we used microarray experiments to analyze gene expression and molecular phenotypic associated with BPH progression, with a particular focus on CI and IL-27/IL-27RA signaling, and verified the microarray data in cell biology experiments. METHODS: Thirty BPH patients’ specimens and clinical parameters were analyzed. BPH patients were divided into two groups based on the average prostate volume (41.5 mL): group 1, ≤40 mL; and group 2, >40 mL. Microarray experiments were conducted to identify differentially expressed genes (DEGs) by applying appropriate biostatistics to normalize and analyze the dataset. The candidate gene (IL27RA) was validated by quantitative reverse transcriptase-PCR (qRT-PCR) and immunohistochemistry (IHC). The interaction of IL27RA with genes involved in canonical inflammation-associated pathways was investigated by cell biology experiments. RESULTS: Eighty-three percent of BPH specimens contained inflammatory infiltrates, and the predominant type was CI. The serum PSA levels and prevalence of CI were higher in group 2. Microarray experiments identified 361 DEGs between these 2 groups. IL27RA was down-regulated and associated with prominent CI in BPH tissues of group 2. Validated by qRT-PCR and IHC, the results showed IL-27RA might modulate CI and progression of BPH. Thus, we investigated the interaction of IL27RA with TLR4, IL6, and IL8, which were involved in inflammation-associated pathways. We found the activation of IL-27RA after IL-27 treatment led to phosphorylation of STAT1 and STAT3 in prostate epithelial cells. By comparative treatments with lipopolysaccharide (LPS), IL-27, or combination, we found that IL-27/IL-27RA signaling suppressed the production of inflammatory cytokines, IL-6 and IL-8, induced by LPS/TLR4 pathway. CONCLUSIONS: Our study revealed that down-regulation of IL27RA in prostate tissue was associated with higher prevalence of CI and BPH progression. IL-27/IL-27RA signaling suppressed the LPS/TLR4 pathway. We conclude the IL-27/IL-27RA signaling might modulate CI and provide potential therapeutic strategies to prevent BPH progression.