Clinical and functional significance of STEAP4-splice variant in CD14+ monocytes in patients with rheumatoid arthritis

Abstract

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.