Clinical and functional significance of STEAP4-splice variant in CD14+ monocytes in patients with rheumatoid arthritis
Clinical and functional significance of STEAP4-splice variant in CD14+ monocytes in patients with rheumatoid arthritis
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DOI：
10.1111/cei.13076
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发表时间：
2018-03-01
影响因子：
4.6
通讯作者：
Sumida, T.
中科院分区：
文献类型：
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作者：
Ebe, H.;Matsumoto, I.;Sumida, T.
肿瘤坏死因子α (TNF)- α诱导脂肪相关蛋白（TIARP）是关节炎模型小鼠炎症的负调节因子。在人类中，前列腺4的六跨膜上皮抗原（STEAP4） （TIARP的人类对应物）也在类风湿性关节炎（RA）患者的CD14（+）单核细胞中表达。最近，在猪肺中观察到高水平的外显子3剪接变体STEAP4 （v-STEAP4）表达。本研究旨在阐明v-STEAP4的表达及其在关节炎发病中的功能作用，并将其与STEAP4进行比较。我们在CD14（+）细胞中鉴定出v-STEAP4。RA患者中STEAP4和v-STEAP4的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患者中使用白细胞介素(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，我们制备了STEAP4和v-STEAP4过表达的人单核细胞系（THP-1）进行功能分析。在过表达v-STEAP4的细胞中，IL-6的产生明显受到抑制，但通过脂多糖（LPS）刺激，tnf - α的产生明显增加。免疫印迹分析显示，LPS刺激后磷酸化（p-）核因子κ B （nf - κ B）增加，核因子κ B抑制剂α (I κ B α)持续降解，而p信号传导和转录激活因子3 （STAT-3）在v-STEAP4刺激下降低。我们确定了RA单核细胞中v-STEAP4的特异性上调。V-STEAP4可能通过NF-kappa B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的产生。
Tumour necrosis factor alpha (TNF)-alpha-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-alpha was increased significantly through lipopolysaccharide (LPS) stimulation. Immunoblot analysis revealed that phosphorylated (p-)nuclear factor kappa B (NF-kappa B) was increased after LPS stimulation and degradation of nuclear factor kappa B inhibitor alpha (I kappa B alpha) 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-alpha and IL-6 through NF-kappa B and STAT-3 pathways, resulting in the generation of RA.