Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Clin Exp Immunol. 2018 Mar;191(3):338-348. doi: 10.1111/cei.13076. Epub 2017 Nov 16.
Tumour necrosis factor alpha (TNF)-α-induced adipose-related protein (TIARP) is a negative regulator of inflammation in arthritis model mice. In humans, six-transmembrane epithelial antigen of prostate 4 (STEAP4) (human counterpart of TIARP) is also expressed in CD14 monocytes from patients with rheumatoid arthritis (RA). Recently, highly levels of exon 3-spliced variant STEAP4 (v-STEAP4) expression have been observed in porcine lung. The aim of this study is to elucidate the expression and functional role of v-STEAP4, comparing it with that of STEAP4, in the pathogenesis of arthritis. We identified v-STEAP4 in CD14 cells. The expression of STEAP4 and v-STEAP4 was higher in patients with RA than in healthy participants. We also found that STEAP4 and v-STEAP4 were correlated positively with C-reactive protein and that their expression was decreased after treatment with an interleukin (IL)-6 antagonist in patients with RA. To investigate further the role of STEAP4 and v-STEAP4, we produced STEAP4 and v-STEAP4 over-expressing human monocytic cell lines (THP-1) for functional analysis. In the v-STEAP4 over-expressing cells, the production of IL-6 was suppressed significantly, but TNF-α was increased significantly through lipopolysaccharide (LPS) stimulation. Immunoblot analysis revealed that phosphorylated (p-)nuclear factor kappa B (NF-κB) was increased after LPS stimulation and degradation of nuclear factor kappa B inhibitor alpha (IκBα) was sustained, whereas p-signal transducer and activator of transcription 3 (STAT-3) was decreased with v-STEAP4. We identified specific up-regulation of v-STEAP4 in RA monocytes. V-STEAP4 might play a crucial role in the production of TNF-α and IL-6 through NF-κB and STAT-3 pathways, resulting in the generation of RA.
肿瘤坏死因子-α诱导的脂肪相关蛋白（TIARP）是关节炎模型小鼠中炎症的负调节剂。在人类中，六跨膜上皮抗原前列腺 4（STEAP4）（TIARP 的人对应物）也在类风湿关节炎（RA）患者的 CD14 单核细胞中表达。最近，在猪肺中观察到高度表达外显子 3 剪接变异体 STEAP4（v-STEAP4）。本研究的目的是阐明 v-STEAP4 的表达和功能作用，并将其与 STEAP4 进行比较，以阐明关节炎的发病机制。我们在 CD14 细胞中鉴定了 v-STEAP4。RA 患者的 STEAP4 和 v-STEAP4 表达高于健康参与者。我们还发现，STEAP4 和 v-STEAP4 与 C 反应蛋白呈正相关，并且在 RA 患者中用白细胞介素（IL）-6 拮抗剂治疗后其表达降低。为了进一步研究 STEAP4 和 v-STEAP4 的作用，我们产生了 STEAP4 和 v-STEAP4 过表达的人类单核细胞系（THP-1）进行功能分析。在 v-STEAP4 过表达细胞中，通过脂多糖（LPS）刺激，IL-6 的产生显著抑制，但 TNF-α 的产生显著增加。免疫印迹分析显示，LPS 刺激后磷酸化（p-）核因子 kappa B（NF-κB）增加，核因子 kappa B 抑制剂 alpha（IκBα）持续降解，而 p-信号转导和转录激活因子 3（STAT-3）减少与 v-STEAP4 相关。我们鉴定了 RA 单核细胞中 v-STEAP4 的特异性上调。v-STEAP4 可能通过 NF-κB 和 STAT-3 途径在 TNF-α 和 IL-6 的产生中发挥关键作用，从而导致 RA 的发生。
