間白素-27/間白素-27受體甲型次單元訊息能經由抑制脂多醣/類鐸受體路徑而調控前列腺良性增生的發炎與進展

羅華成^{1, 5}、于大雄²、高鴻偉³、蔡孟勳⁴、莊曜宇⁵。

¹國防醫學院三軍總醫院松山分院泌尿外科；三軍總醫院²泌尿外科，³病理學科；⁴國立台灣大學生物科技研究所，⁵生醫電子與資訊學研究所。

Interleukin-27/ Interleukin-27 receptor α subunit Signaling May Modulate Inflammation and Progression of Benign Prostatic Hyperplasia via Suppressing the LPS/TLR4 Pathway

Hua-Cheng Lo^1,5, Dah-Shyong Yu², Hong-Wei Gao³, Mong-Hsun Tsai⁴, Eric Y. Chuang⁵.

¹Division of Urological Surgery, Department of Surgery, Tri-Service General Hospital Song-Shan Branch, National Defense Medical Center, Taipei, Taiwan; ²Division of Urological Surgery, Department of Surgery, ³Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; ⁴Institute of Biotechnology, ⁵Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.

Purpose:

Benign prostatic hyperplasia (BPH) is the most common urologic disease affecting aging men. The pathogenesis of BPH is multi-factorial, and chronic inflammation (CI) is considered a central mechanism, albeit an unclear one. Interleukin-27 (IL-27) signaling has been suggested as a modulator in autoimmune and inflammatory conditions like BPH. In this study, we used microarray experiments to analyze gene expression in BPH tissues and compared phenotypic properties between different degrees of BPH. We analyzed the molecular signatures associated with BPH progression, with a particular focus on CI and the role of IL-27 and its receptor α subunit, IL-27RA. Finally, we verified the expression data in cell biological experiments.

Materials and Methods:

 Thirty specimens of BPH were obtained from symptomatic patients undergoing surgery. Clinical parameters including age, prostate volume, and serum level of prostate specific antigen (PSA) were analyzed. BPH patients were divided into two groups based on the average prostate volume (41.5 mL): group 1, volume ≦ 40 mL; and group 2, volume > 40 mL. Microarray experiments were conducted, and differential gene expression was identified by applying appropriate biostatistics to normalize and analyze the dataset. The candidate genes with differential expression between the 2 groups were validated by quantitative reverse transcriptase-PCR (qRT-PCR) and immunohistochemistry (IHC). To further define the involvement of IL27RA in CI of BPH, 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 (64%). The serum PSA levels and prevalence of CI were higher in group 2 compared with group 1. Microarray experiments identified 361 differentially expressed genes between the 2 groups. IL27RA was down-regulated in group 2, and was associated with prominent CI in BPH tissues. Validated by qRT-PCR and IHC, the results suggested IL-27RA might be involved in modulation of CI and progression of BPH. Thus, cell biology experiments were performed to investigate the interaction of IL27RA with TLR4, IL6, and IL8, which are known to be involved in canonical inflammation-associated pathways. We found that IL-27RA can be activated upon IL-27 stimulation, which led to phosphorylation of STAT1/STAT3 and indicated the intact IL-27/IL-27RA signaling in prostate epithelial cells. By comparative treatments with LPS, IL-27, or combination, we found that activated IL-27/IL-27RA signaling could suppress the production of inflammatory cytokines, IL-6 and IL-8.

Conclusion:

Our study revealed that down-regulation of IL27RA in prostate tissue was associated with higher prevalence of CI and progression of BPH. IL-27/IL-27RA signaling suppressed the production of inflammatory cytokines. Therefore, we conclude that IL-27/IL-27RA signaling may modulate inflammatory responses, and might provide a potential therapeutic strategy to prevent BPH progression.