Vol.22 No.1

Original Article

Six-transmembrane epithelial antigen of prostate4 (STEAP4) is a tumor necrosis factor alpha-induced protein that regulates IL-6, IL-8, and cell proliferation in synovium from patients with rheumatoid arthritis

Authors

Yoko Tanaka1 , Isao Matsumoto1 , Keiichi Iwanami1 , Asuka Inoue1 , Reiko Minami1 , Naoto Umeda1 , Akihiro Kanamori2 , Naoyuki Ochiai2 , Keiji Miyazawa3 , Makoto Sugihara1 , Taichi Hayashi1 , Daisuke Goto1, Satoshi Ito1, Takayuki Sumida1

  • Division of Clinical Immunology, Doctoral Program in Clinical Science, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan
  • Orthopedic Surgery, Doctoral Program in Clinical Science, Graduate School of Comprehensive Human Science, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8575, Japan
  • Discovery Research III, Research and Development, Kissei Pharmaceutical Company, Nagano, Japan
Received:

10 February 2011

Accepted:

16 May 2011

Published online:

3 June 2011

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Abstract

Human six-transmembrane epithelial antigen of prostate4 (STEAP4), an ortholog of mouse tumor necrosis factor-a-induced adipose-related protein (TIARP), plays a role in tumor necrosis factor (TNF)-dependent arthritis models. However, its role in rheumatoid arthritis (RA) is still obscure. This study explored such a role for STEAP4. The expressions of STEAP4, TNFα, and IL-6 were compared in synovia of RA and osteoarthritis patients. STEAP4 induction was examined in TNFα-stimulated fibroblast-like synoviocytes (FLS) in vitro. FLS (with/without TNFα stimulation) were also analyzed for IL-6 expression after STEAP4 knockdown, using siRNA or transfection with STEAP4-plasmid DNA. IL-8, cell proliferation, and apoptosis were also evaluated in STEAP4-overexpressing FLS. The expression of STEAP4 in joints correlated with TNFα expression, specifically in RA synovium. In the cultured FLS, STEAP4 protein expression was augmented by TNFα activation, and localized in endosomal/lysosomal compartments. STEAP4 downregulation by siRNA enhanced the expression of IL-6 mRNA, while STEAP4 overexpression suppressed IL-6 and IL-8 expression, inhibited cell proliferation, and induced apoptosis via caspase-3. The results indicated that human STEAP4 is regulated by TNFα in synovium, where it controls IL-6 secretion and proliferation of FLS, suggesting that STEAP4 might potentially suppress the pathogenesis of TNFα-induced arthritis such as RA.

Key words

Glucose-6-phosphate-isomerase - Rheumatoid arthritis - STEAP4 - TIARP - TNFα