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

Summary

Tumor necrosis factor alpha (TNFα)-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 exon3-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 positively correlated with C-reactive protein and that their expression was decreased after treatment with an interleukin (IL)-6 antagonist in patients with RA. To further investigate the role of STEAP4 and v-STEAP4, we produced STEAP4 and v-STEAP4 overexpressing human monocytic cell lines (THP-1) for functional analysis. In the v-STEAP4 overexpressing cells, the production of IL-6 was significantly suppressed, but TNFα was significantly increased through lipopolysaccharide (LPS) stimulation. Immunoblot analysis revealed that phosphorylated (p-)NF-κB was increased after LPS stimulation and degradation of IκBα was sustained, whereas p-STAT3 was decreased with v-STEAP4. We identified specific upregulation of v-STEAP4 in RA monocytes. V-STEAP4 might play a crucial role in the production of TNFα and IL-6 through NF-κB and STAT3 pathways, resulting in the generation of RA. This article is protected by copyright. All rights reserved.