自己免疫性関節炎におけるTNFα-induced adipose-related protein (TIARP）の新たな作用機序
関節リウマチ（RA）は，関節滑膜を主病変部とする炎症性疾患であり，病因として異常増殖した滑膜細胞などから産生される炎症性サイトカインTNFαやIL-6の過剰な分泌が考えられている．近年このTNFαやIL-6をターゲットとした生物学的製剤が開発され，RAの治療に顕著な成績を上げている．glucose-6-phosphate isomerase (GPI）は関節炎自然発症モデルであるK/BxNマウスの自己抗原として同定されたユビキタスに存在する解糖系酵素である．この合成GPI蛋白をDBA/1マウスに免疫することにより早期に関節炎を惹起できる．このモデルを用いて関節炎病態に寄与する分子を探索するため...
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| Published in | 日本臨床免疫学会会誌 Vol. 35; no. 1; pp. 51 - 55 |
|---|---|
| Main Authors | , , , |
| Format | Journal Article |
| Language | Japanese |
| Published |
日本臨床免疫学会
2012
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| Online Access | Get full text |
| ISSN | 0911-4300 1349-7413 |
| DOI | 10.2177/jsci.35.51 |
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| Abstract | 関節リウマチ（RA）は，関節滑膜を主病変部とする炎症性疾患であり，病因として異常増殖した滑膜細胞などから産生される炎症性サイトカインTNFαやIL-6の過剰な分泌が考えられている．近年このTNFαやIL-6をターゲットとした生物学的製剤が開発され，RAの治療に顕著な成績を上げている．glucose-6-phosphate isomerase (GPI）は関節炎自然発症モデルであるK/BxNマウスの自己抗原として同定されたユビキタスに存在する解糖系酵素である．この合成GPI蛋白をDBA/1マウスに免疫することにより早期に関節炎を惹起できる．このモデルを用いて関節炎病態に寄与する分子を探索するためにDNAマイクロアレイを試行したところ，TNFα-induced adipose-related protein (TIARP）が関節炎マウス脾臓で高発現することを明らかとした．さらに我々は，関節局所においてもその増強を認め，腫脹の程度に合わせて変動することを見出した．また我々はTIARPが脾臓CD11b陽性細胞（マクロファージ，好中球）ならびに関節の滑膜細胞に局在することを明らかとした．TIARPのヒトorthologであるsix-transmembrane epithelial antigen of prostate 4 (STEAP4）蛋白も，マウス同様にRA患者滑膜細胞に発現していた．本稿では，自己免疫性関節炎およびヒトRA病態において新規関節炎抑制分子と考えられるTIARP/STEAP4分子について概説し，我々の見出したTIARP/STEAP4の新たな機能について紹介する． |
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| AbstractList | 関節リウマチ（RA）は，関節滑膜を主病変部とする炎症性疾患であり，病因として異常増殖した滑膜細胞などから産生される炎症性サイトカインTNFαやIL-6の過剰な分泌が考えられている．近年このTNFαやIL-6をターゲットとした生物学的製剤が開発され，RAの治療に顕著な成績を上げている．glucose-6-phosphate isomerase (GPI）は関節炎自然発症モデルであるK/BxNマウスの自己抗原として同定されたユビキタスに存在する解糖系酵素である．この合成GPI蛋白をDBA/1マウスに免疫することにより早期に関節炎を惹起できる．このモデルを用いて関節炎病態に寄与する分子を探索するためにDNAマイクロアレイを試行したところ，TNFα-induced adipose-related protein (TIARP）が関節炎マウス脾臓で高発現することを明らかとした．さらに我々は，関節局所においてもその増強を認め，腫脹の程度に合わせて変動することを見出した．また我々はTIARPが脾臓CD11b陽性細胞（マクロファージ，好中球）ならびに関節の滑膜細胞に局在することを明らかとした．TIARPのヒトorthologであるsix-transmembrane epithelial antigen of prostate 4 (STEAP4）蛋白も，マウス同様にRA患者滑膜細胞に発現していた．本稿では，自己免疫性関節炎およびヒトRA病態において新規関節炎抑制分子と考えられるTIARP/STEAP4分子について概説し，我々の見出したTIARP/STEAP4の新たな機能について紹介する． |
| Author | 住田, 孝之 井上, 明日香 松本, 功 田中, 陽子 |
| Author_xml | – sequence: 1 fullname: 住田, 孝之 organization: 筑波大学医学医療系内科（膠原病・リウマチ・アレルギー） – sequence: 1 fullname: 井上, 明日香 organization: 筑波大学医学医療系内科（膠原病・リウマチ・アレルギー） – sequence: 1 fullname: 松本, 功 organization: 筑波大学医学医療系内科（膠原病・リウマチ・アレルギー） – sequence: 1 fullname: 田中, 陽子 organization: 筑波大学医学医療系内科（膠原病・リウマチ・アレルギー） |
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| References | 17) Kralisch S, et al. : Interleukin-1beta is a positive regulator of TIARP/STAMP2 gene and protein expression in adipocytes in vitro. FEBS Lett. 583 : 1196-1200, 2009. 7) Tanaka-Watanabe Y, et al. : B cell play crucial role as antigen presenting cells and collaborating with inflammatory cytokines in glucose-6-phosphate isomerase. Clin Exp Immunol. 155 : 285-294, 2009. 6) Matsumoto I, et al. : Therapeutic effects of antigocies to tumor necrosis factor-α, interleukin-6 and cytotoxic T-lymphocyte antigen 4 immunoglobulin in mice with glucose-6-phosphate isomerase induced arthritis. Arthritis Res Ther. 10 : 4R66, 2008. 13) Chu CQ, et al. : Localization of tumor necrosis factor-alpha in synovial tissues and at the cartilage pannus junction in patients with rheumatoid arthritis. Arthritis Rheum. 34 : 1125-1132, 1991. 1) Feldmann M, Maini SR. : Role of cytokines in rheumatoid arthritis. Immunol Rev. 223 : 7-9, 2008. 22) Ohgami RS, et al. : The STEAP proteins are metalloreductases. Blood. 108 : 1388-1394, 2006. 24) Zhang CM, et al. : Downregulation of STEAP4, a highly-expressed TNF-alpha-inducible gene in adiposetissue, is associated with obesity in humans. Acta Pharmacol Sin. 29 : 587-592, 2008. 25) Wang ZH, et al. : Expression of STAMP2 in monocytes associates with cardiovascular alterations. Eur J Clin Invest. 40 : 490-496, 2010. 12) Husby G, Williams RC. : Synovial localization of tumor necrosis factor in patients with rheumatoid arthritis. J Autoimmun. 1 : 363-371, 1988. 11) Charles P, et al. : Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF alpha therapy in rheumatoid arthritis. J Immunol. 163 : 1521-1528, 1999. 23) Scanchez-Pulido L, et al. : ACRATA : a novel electrom transfer domain associated to apoptosis and cancer. BMC Cancer. 4 : 98, 2004. 10) Hopkins SJ, Meager A. : Cytokines in synovial fluid : II. The presence of tumor necrosis factor and interferon. Clin Exp Immunol. 73 : 88-92, 1988. 15) Moldes M, et al. : Tumor Necrosis Factor-α-induced Adipose-related Protein (TIARP), a cell-surface protein that is highly induced by Tumor Necrosis Factor-α and adipose conversion. J Bio Chem. 276 : 33938-33946, 2001. 19) Wellen KE, et al. : Coordinated regulation of nutrient and inflammatory response by STAMP2 is essential for metabolic homeostasis. Cell 129 : 537-548, 2007. 4) Matsumoto I, et al. : Arthritis provoked by linked T and B cell recognition of a plycolytic enzyme. Science. 286 : 1732-1735, 1999. 5) Schubert D, et al. : Immunization with glucose-6-phosphate isomerase induces T cell-dependent peripheral polyarthritis in genetically unaltered mice. J Immunol. 172 : 4503-4509, 2004. 20) Hubert RS, et al. : STEAP : a prostate-specific cell-antigen highly expressed in human prostate tumors. Proc Natl Acad Sci U.S.A. 96 : 14523-14528, 1999. 27) Tanaka Y, et al. : Six-transmembrane epithelial antigen of prostate 4 (STEAP4) is expressed on monocytes/neutrophils, and is regulated by TNF antagonist in patients with rheumatoid arthritis. Clin Exp Rheumatol. In press. 3) Mima Y, et al. : Clinical value of blocking IL-6 receptor. Curr Opin Rheumatol. 21 : 224-230, 2009. 21) Porkka KP, et al. : Cloning and characterization of a novel six-transmemrane protein STEAP2, expressed in normal and malignant prostate. Lab Invest. 82 : 1573-1582, 2002. 14) Inoue A, et al. : Tumor necrosis factor α-induced adipose-related protein expression in experimental arthritis and in rheumatoid arthritis. Arthritis Res Ther. 11 : R118, 2009. 2) Taylor PC, et al. : Anti-TNF biologic agents : stil the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol. 5 : 578-582, 2009. 9) Wooley PH, et al. : Influence of a recombinant human soluble tumor-necrosis-factor recepor Fc fusion protein on type-II collagen-induced arthritis in mice. J Immunol. 151 : 6602-6607, 1993. 16) Fasshauer M, et al. : Interleukin-6 is a positive regulator of tumor necrosis factor α-induced adipose-related protein in 3T3-L1 adipocytes. FEBS. 560 : 153-157, 2004. 26) Tanaka Y, et al. : Six-transmembrane epithelial antigen of prostate 4 (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. Mod Rheumatol. In press. 18) Sparna T, et al. : Genome-wide comparison between IL-17 and combined TNF-alpha/IL-17 induced genes in primary murine hepatocytes. BMC Genomics. 11 : 226, 2010. 8) Iwanami K, et al. : Crucial role of IL-6/IL-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomerase. Arthritis Rheum, 58 : 754-763, 2008. |
| References_xml | – reference: 2) Taylor PC, et al. : Anti-TNF biologic agents : stil the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol. 5 : 578-582, 2009. – reference: 14) Inoue A, et al. : Tumor necrosis factor α-induced adipose-related protein expression in experimental arthritis and in rheumatoid arthritis. Arthritis Res Ther. 11 : R118, 2009. – reference: 15) Moldes M, et al. : Tumor Necrosis Factor-α-induced Adipose-related Protein (TIARP), a cell-surface protein that is highly induced by Tumor Necrosis Factor-α and adipose conversion. J Bio Chem. 276 : 33938-33946, 2001. – reference: 21) Porkka KP, et al. : Cloning and characterization of a novel six-transmemrane protein STEAP2, expressed in normal and malignant prostate. Lab Invest. 82 : 1573-1582, 2002. – reference: 27) Tanaka Y, et al. : Six-transmembrane epithelial antigen of prostate 4 (STEAP4) is expressed on monocytes/neutrophils, and is regulated by TNF antagonist in patients with rheumatoid arthritis. Clin Exp Rheumatol. In press. – reference: 11) Charles P, et al. : Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF alpha therapy in rheumatoid arthritis. J Immunol. 163 : 1521-1528, 1999. – reference: 22) Ohgami RS, et al. : The STEAP proteins are metalloreductases. Blood. 108 : 1388-1394, 2006. – reference: 20) Hubert RS, et al. : STEAP : a prostate-specific cell-antigen highly expressed in human prostate tumors. Proc Natl Acad Sci U.S.A. 96 : 14523-14528, 1999. – reference: 6) Matsumoto I, et al. : Therapeutic effects of antigocies to tumor necrosis factor-α, interleukin-6 and cytotoxic T-lymphocyte antigen 4 immunoglobulin in mice with glucose-6-phosphate isomerase induced arthritis. Arthritis Res Ther. 10 : 4R66, 2008. – reference: 3) Mima Y, et al. : Clinical value of blocking IL-6 receptor. Curr Opin Rheumatol. 21 : 224-230, 2009. – reference: 25) Wang ZH, et al. : Expression of STAMP2 in monocytes associates with cardiovascular alterations. Eur J Clin Invest. 40 : 490-496, 2010. – reference: 23) Scanchez-Pulido L, et al. : ACRATA : a novel electrom transfer domain associated to apoptosis and cancer. BMC Cancer. 4 : 98, 2004. – reference: 13) Chu CQ, et al. : Localization of tumor necrosis factor-alpha in synovial tissues and at the cartilage pannus junction in patients with rheumatoid arthritis. Arthritis Rheum. 34 : 1125-1132, 1991. – reference: 7) Tanaka-Watanabe Y, et al. : B cell play crucial role as antigen presenting cells and collaborating with inflammatory cytokines in glucose-6-phosphate isomerase. Clin Exp Immunol. 155 : 285-294, 2009. – reference: 17) Kralisch S, et al. : Interleukin-1beta is a positive regulator of TIARP/STAMP2 gene and protein expression in adipocytes in vitro. FEBS Lett. 583 : 1196-1200, 2009. – reference: 10) Hopkins SJ, Meager A. : Cytokines in synovial fluid : II. The presence of tumor necrosis factor and interferon. Clin Exp Immunol. 73 : 88-92, 1988. – reference: 19) Wellen KE, et al. : Coordinated regulation of nutrient and inflammatory response by STAMP2 is essential for metabolic homeostasis. Cell 129 : 537-548, 2007. – reference: 26) Tanaka Y, et al. : Six-transmembrane epithelial antigen of prostate 4 (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. Mod Rheumatol. In press. – reference: 5) Schubert D, et al. : Immunization with glucose-6-phosphate isomerase induces T cell-dependent peripheral polyarthritis in genetically unaltered mice. J Immunol. 172 : 4503-4509, 2004. – reference: 16) Fasshauer M, et al. : Interleukin-6 is a positive regulator of tumor necrosis factor α-induced adipose-related protein in 3T3-L1 adipocytes. FEBS. 560 : 153-157, 2004. – reference: 4) Matsumoto I, et al. : Arthritis provoked by linked T and B cell recognition of a plycolytic enzyme. Science. 286 : 1732-1735, 1999. – reference: 12) Husby G, Williams RC. : Synovial localization of tumor necrosis factor in patients with rheumatoid arthritis. J Autoimmun. 1 : 363-371, 1988. – reference: 9) Wooley PH, et al. : Influence of a recombinant human soluble tumor-necrosis-factor recepor Fc fusion protein on type-II collagen-induced arthritis in mice. J Immunol. 151 : 6602-6607, 1993. – reference: 18) Sparna T, et al. : Genome-wide comparison between IL-17 and combined TNF-alpha/IL-17 induced genes in primary murine hepatocytes. BMC Genomics. 11 : 226, 2010. – reference: 1) Feldmann M, Maini SR. : Role of cytokines in rheumatoid arthritis. Immunol Rev. 223 : 7-9, 2008. – reference: 8) Iwanami K, et al. : Crucial role of IL-6/IL-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomerase. Arthritis Rheum, 58 : 754-763, 2008. – reference: 24) Zhang CM, et al. : Downregulation of STEAP4, a highly-expressed TNF-alpha-inducible gene in adiposetissue, is associated with obesity in humans. Acta Pharmacol Sin. 29 : 587-592, 2008. |
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| Title | 自己免疫性関節炎におけるTNFα-induced adipose-related protein (TIARP）の新たな作用機序 |
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