title: 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.
abstract: Human six-transmembrane epithelial antigen of prostate4 (STEAP4), an ortholog of mouse tumor necrosis factor-α-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.
authors.affiliation: 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.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Isao
authors.initials: I
authors.lastname: Matsumoto
authors.forename: Keiichi
authors.initials: K
authors.lastname: Iwanami
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.forename: Reiko
authors.initials: R
authors.lastname: Minami
authors.forename: Naoto
authors.initials: N
authors.lastname: Umeda
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kanamori
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Ochiai
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyazawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Sugihara
authors.forename: Taichi
authors.initials: T
authors.lastname: Hayashi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Goto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ito
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D020370:Osteoarthritis, Knee / Q000378:metabolism / Q000473:pathology; D010088:Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D015850:Interleukin-6; D016209:Interleukin-8; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D010088:Oxidoreductases; C503310:STEAP4 protein, human