Positive and negative regulation of macrophage/ dendritic cell functions by novel paired receptors

• Project/Area Number: 18590256
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Gunma University
• Principal Investigator: OKAZAWA Hideki Gunma University, Institute for Molecular and Cellular Regulation, Assistant professor (80334126)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000); Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: Dendritic cell / Macrophage / SHPS-1 / Phagocytosis / Cytokine / チロシンリン酸化 / チロシンホスファターゼ

Research Abstract

SHPS-1 is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is expressed on the surface of dendritic cells (DCs) and macrophages. We have now shown that forced expression in mouse RAW264.7 macrophages of a mutant version (SHPS-1-4F) of mouse SHPS-1, in which four tyrosine phosphorylation sites are replaced by phenylalanine, markedly promoted FcγR-mediated phagocytosis of mouse RBCs or SRBCs. In addition, expression of SHPS-1-4F promoted the production of TNFα and IL-6 induced by LPS or poly(I:C) in RAW cells. These data suggest that inhibition by SHPS-1 of phagocytosis in macrophages is mediated, at least in part, in a manner independent of the trans-interaction between CD47 and SHPS-1 and SHPS-1 negatively regulates TLR4- or TLR3- dependent cytokine production through inhibition of NFkB-dependent signaling.
We also show that mice that express a mutant form of SHPS-1 lacking most of the cytoplasmic region are resistant to experimental autoimmune encephalomyelitis (EAE) in response to immunization with a peptide derived from myelin oligodendrocyte glycoprotein [MOG(35-55)]. The MOG(35-55)-induced proliferation of, and production of IFN-γ, IL-2, and IL-17 by, T cells from immunized SHPS-1 mutant mice were reduced compared with those apparent for wild-type cells. These results show that SHPS-1 on DCs is essential for priming of naive T cells and the development of EAE. SHPS-1 is thus a potential therapeutic target in inflammatory disorders of the central nervous system and other autoimmune diseases.

Research Products

• [Journal Article] Negative regulation by SHPS-1 of Toll-like receptor-dependent proinflammatory cytokine production in macrophages. (2008)
  • Author(s): Miyake, A., 他
  • Journal Title: Genes to Cells 13 Pages: 209-219
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Negative regulation by SHPS-1 of Toll-like receptor-dependent proinflammatory cytokine production in macrophages (2008)
  • Author(s): Miyake, A., Murata, Y., Okazawa. H., Ikeda, H., Niwayama, Y., Ohnishi, H., Hirata, Y., Matozaki, T.
  • Journal Title: Genes to Cells 13 Pages: 209-219
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Negative regulation by SHPS-1 of Toll-like receptor-dependent proinflammatory cytokine production in macrophages (2008)
  • Author(s): Miyake, A., 他
  • Journal Title: Genes to Cells 13 Pages: 209-219
  • Peer Reviewed
• [Journal Article] Resistance to experimental autoimmune encephalomyelitis and impaired T cell priming by dendritic cells in Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 mutant mice. (2007)
  • Author(s): Tomizawa, T., 他
  • Journal Title: Journal of Immunology 179 Pages: 869-877
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Regulation by Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 of α-Galactosylceramide-induced antimetastatic activity and Th1 and Th2 responses of NKT cells. (2007)
  • Author(s): Okajo, J., 他
  • Journal Title: Journal of Immunology 178 Pages: 6164-6172
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Resistance to experimental autoimmune encephalomyelitis and impaired T cell priming by dendritic cells in Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 mutant mice (2007)
  • Author(s): Tomizawa, T., Kaneko, Y., Kaneko, Y., Saito, Y., Ohnishi, H., Okajo, J., Okuzawa, C., Ishikawa-Sekigami, T., Murata, Y., Okazawa. H., Okamoto, K., Nojima, Y., Matozaki, T.
  • Journal Title: Journal of Immunology 179 Pages: 869-877
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regulation by Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 of α-Galactosylceramide-induced antimetastatic activity and Th1 and Th2 responses of NKT cells (2007)
  • Author(s): Okajo, J., Kaneko, Y., Murata, Y., Tomizawa, T., Okuzawa, C., Saito, Y., Kaneko, Y., Ishikawa-Sekigami, T., Okazawa. H., Ohnishi, H., Matozaki, T., and Nojima, Y.
  • Journal Title: Journal of Immunology 178 Pages: 6164-6172
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Resistance to experimental autoimmune encephalomyelitis and impaired Tcell priming by dendritic cells in Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 mutant mice (2007)
  • Author(s): Tomizawa, T., 他
  • Journal Title: Journal of Immumlogy 179 Pages: 869-877
  • Peer Reviewed
• [Journal Article] Regulation by Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 of α-Galactosylceramide-induced antimetastatic activity and Th1 and Th2 responses of NKT cells (2007)
  • Author(s): Okajo, J., 他
  • Journal Title: Journal of Immunology 178 Pages: 6164-6172
  • Peer Reviewed
• [Journal Article] Regulation by src homology 2 domain-containing protein tyrosine phosphatase substrate-1 of _-Galactosylceramide-induced antimetastatic activity and Th1 and Th2 responses of NKT cells. (2007)
  • Author(s): Okajo, J. 他
  • Journal Title: Journal of Immunology (印刷中)
• [Journal Article] Mutational analysis of the mechanism of negative regulation by Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 of phagocytosis in macrophages. (2006)
  • Author(s): Ikeda, H., 他
  • Journal Title: Journal of Immunology 177 Pages: 3123-3132
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 regulates the induction of Langerhans cell maturation. (2006)
  • Author(s): Fukunaga, A., 他
  • Journal Title: European Journal of Immunology 3 Pages: 3216-3226
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Mutational analysis of the mechanism of negative regulation by Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 of phagocytosis in macrophages (2006)
  • Author(s): Ikeda, H., Okazawa. H., Ohnishi, H., Murata, Y., Oldenborg, P. -A., and Matozaki, T.
  • Journal Title: Journal of Immunology 177 Pages: 3123-3132
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 regulates the induction of Langerhans cell maturation (2006)
  • Author(s): Fukunaga, A., Nagai, H., Yu, X., Oniki, S., Okazawa. H., Motegi, S., Suzuki, R., Honma, N., Matozaki, T., Nishigori, C., and Horikawa, T.
  • Journal Title: European Journal of Immunology 3 Pages: 3216-3226
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mutational Analysis of the Mechanism of Negative Regulation by SRC homology 2 domain-containing protein tyrosine phosphatase substrate-1 of Phagocytosis in Macrophages. (2006)
  • Author(s): Ikeda, H. 他
  • Journal Title: Journal of Immunology 177巻・5号 Pages: 3123-3132
• [Journal Article] Src homology 2 domain-containing protein tyrosine phos-phatase substrate 1 regulates the induction of Lancerhans cell maturation. (2006)
  • Author(s): Fukunaga, A. 他
  • Journal Title: European Journal of Immunology 3巻・12号 Pages: 3216-3226
• [Journal Article] CD47 promotes neuronal development through Src- and FRG/Vav2-mediated activation of Rac and Cdc42. (2006)
  • Author(s): Murata, T., 他
  • Journal Title: Journal of Neuroscience 26巻・48号 Pages: 1239-1240
• [Journal Article] Enhanced phagocytosis of CD47-deficient red blood cells by splenic macrophages requires SHPS-1. (2006)
  • Author(s): Ishikawa-Sekigami, T. 他
  • Journal Title: Biochemical and Biophysical Research Communication 343巻・4号 Pages: 1197-1200
• [Journal Article] CD47 regulation of epithelial cell spreading and migration, and its signal transduction. (2006)
  • Author(s): Shinohara M. 他
  • Journal Title: Cancer Science 97巻・9号 Pages: 889-895
• [Presentation] SHPS-1によるToll-like receptorを介したサイトカイン産生の制御 (2007)
  • Author(s): 三宅 敦子, 他
  • Organizer: BMB2007第30回日本分子生物学会年会第80回日本生化学会大会 合同大会
  • Place of Presentation: パシフィコ横浜ヨコハマグランドインターコンチネンタルホテル(横浜)
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] CD47-SHPS-1シグナルシステムの機能とその分子機構 (2007)
  • Author(s): 的崎 尚, 他
  • Organizer: BMB2007第30回日本分子生物学会年会第80回日本生化学会大会 合同大会
  • Place of Presentation: パシフィコ横浜ヨコハマグランドインターコンチネンタルホテル(横浜)
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Regulation by SHPS-1 of skin immunity and of Toll-like receptor-mediated cytokine production (2007)
  • Author(s): Motegi, S., 他
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪(東京)
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] An essential role of SHPS-1 in proper development of dendritic cells for induction of Th17-mediated autoimmune diseases (2007)
  • Author(s): Saito, Y., 他
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪(東京)
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Regulation by SHPS-1 of Toll-like receptor-mediated cytokine production in macrophages (2007)
  • Author(s): Miyake, A., 他
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪(東京)
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] SHPS-1による皮膚免疫とToll様受容体を介したサイトカイン産生の制御 (2007)
  • Author(s): Motegi, S., 他
  • Organizer: 日本癌学会第66回総会
  • Place of Presentation: パシフィコ横浜(横浜)
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] マクロファージにおけるSHPS-1によるTol1-1ike receptorを介したサイトカイン産生の制御 (2007)
  • Author(s): Miyake, A., 他
  • Organizer: 第6回生体機能研究会
  • Place of Presentation: 箱根プリンスホテル・レークサイドアネックス(箱根)
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Negative regulation by SHPS-1 of Toll-like receptor mediated cytokine production by macrophages (2007)
  • Author(s): Miyake, A., 他
  • Organizer: EuroPhosphatases2007 "Protein Phosphatases in Health and Disease"
  • Place of Presentation: Aveiro Portugal
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] An essential role of SHPS-1 in development of Th17-mediated inflammatory autoimmune diseases (2007)
  • Author(s): Ohnishi, H., 他
  • Organizer: EuroPhosphatases2007 "Protein Phosphatases in Health and Disease"
  • Place of Presentation: Aveiro Portugal
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Roles of SHPS-1 and its family protein SIRPβ in regulation of macrophage phagocytosis (2007)
  • Author(s): Okazawa, H., 他
  • Organizer: 第59回日本細胞生物学会大会第40回日本発生生物学会大会合同大会
  • Place of Presentation: 福岡国際会議場(福岡)
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Roles of SHPS-1 and its family protein SIRPβ in regulation of macrophage phagocytosis (2007)
  • Author(s): Okazawa, H., Motegi, S., Ikeda, H., Morimoto, N., Ishikawa-Sekigami, T., Hayashi, A., Murata, Y., Ohnishi, H., Matozaki, T.
  • Organizer: The 59th annual meeting of the Japan Society for Cell Biology The 40th annual mmeting of the Japanese Society of Developmental Biologists
  • Place of Presentation: Fukuoka
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] An essential role of SHPS-1 in development of Th17-mediated inflammatory autoimmune diseases (2007)
  • Author(s): Ohnishi, H., Kaneko, Y., Okazawa, H., Murata, Y., Matozaki, T.
  • Organizer: EuroPhosphatases 2007 "Protein Phosphatases in Health and Disease"
  • Place of Presentation: Aveiro Portugal
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Negative regulation by SHPS-1 of Toll-like receptor mediated cytokine production by macrophages (2007)
  • Author(s): Miyake, A., Murata, Y., Okazawa, H., Ikeda, H., Onhishi, H., Hirata, Y., Matozaki, T.
  • Organizer: EuroPhosphatases 2007 "Protein Phosphatases in Health and Disease"
  • Place of Presentation: Aveiro Portugal
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Negative regulation by SHPS-1 of Toll-like receptor-mediated cytokine production by macrophages (2007)
  • Author(s): Miyake, A., Murata, Y., Okazawa, H., Ikeda, H., Niwayama, Y., Onhishi, H., Hirata, Y., Matozaki, T.
  • Organizer: The 6th Conference of Biofunctions
  • Place of Presentation: Hakone
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Regulation by SHPS-1 of skin immunity and of Toll-like receptor-mediated cytokine production (2007)
  • Author(s): Motegi, S., Okazawa, H., Kobayashi, H., Murata, Y., Ohnishi, H., Ishikawa, O., Matozaki, T.
  • Organizer: The 66th annual meeting of the Japanese Cancer Asociation
  • Place of Presentation: PacificoYokohama
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Regulation by SHPS-1 of Toll-like receptor-mediated cytokine production by macrophages (2007)
  • Author(s): Miyake, A., Murata, Y., Okazawa, H., Ikeda, H., Onhishi, H., Hirata, Y., Matozaki, T.
  • Organizer: The 37th annual meeting of the Japanese Society for Immunology
  • Place of Presentation: Tokyo
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] An essential role of SHPS-1 in proper development of dendritic cells for induction of Th17-mediated autoimmune diseases (2007)
  • Author(s): Saito, Y., Kaneko, Y., Kaneko, Y., Okuzawa, C., Sekigami, T., Okajo, J., Tomizawa, T., Murata, Y., Okazawa, H., Onhishi, H., Matozaki, T., Nojima, Y.
  • Organizer: The 37th annual meeting of the Japanese Society for Immunology
  • Place of Presentation: Tokyo
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Regulation by SHPS-1 of skin immunity and of Toll-like receptor-mediated cytokine production (2007)
  • Author(s): Motegi, S., Okazawa, H., Kobayashi, H., Murata, Y., Ohnishi, H., Ishikawa, O., Matozaki, T.
  • Organizer: The 37th annual meeting of the Japanese Society for Immunology
  • Place of Presentation: Tokyo
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Functions and the molecular mechanism of the CD47-SHPS-1 System (2007)
  • Author(s): Matozaki T., Ohnishi, H., Okazawa, H., Murata, Y.
  • Organizer: BMB2007
  • Place of Presentation: Pacifico Yokohama
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Regulation by SHPS-1 of Toll-like receptor-mediated cytokine production by macrophages (2007)
  • Author(s): Miyake, A., Murata, Y., Okazawa, H., Ikeda, H., Onhishi, H., Hirata, Y., Matozaki, T.
  • Organizer: BMB2007
  • Place of Presentation: Pacifico Yokohama
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] An essential role of SHPS-1 in development of Th17-mediated inflammatory autoimmune diseases (2007)
  • Author(s): Ohnishi, H., 他
  • Organizer: EuroPhosphatases 2007"Protein Phosphatases in Health and Disease"
  • Place of Presentation: Aveiro Portugal
• [Presentation] Negative regulation by SHPS-l of Toll-like receptor mediated cytokine production by macrophages (2007)
  • Author(s): Miyake, A., 他
  • Organizer: EuroPhosphatases 2007 "Protein Phosphatases in Health and Disease"
  • Place of Presentation: Aveiro Portugal
• [Presentation] マクロファージにおけるSHPS-1によるToll-like receptorを介したサイトカイン産生の制御 (2007)
  • Author(s): Miyake, A., 他
  • Organizer: 第6回生体機能研究会
  • Place of Presentation: 箱根プリンスホテル・レークサイドアネックス(箱根)
• [Presentation] SHPS-1 たよる皮膚免疫とToll様受容体を介したサイトカイン産生の制御 (2007)
  • Author(s): Motegi, S., 他
  • Organizer: 日本癌学会第66回総会
  • Place of Presentation: パシフィコ横浜(横浜)
• [Presentation] Regulation by SHPS-l of skin immunity and of Toll-like receptor-mediated cytokine production (2007)
  • Author(s): Motegi, S., 他
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: グランドプリンスホテル新高輪(東京)
• [Presentation] CD47-SHPS-1シグナルシステムの機能とその分子機構 (2007)
  • Author(s): 的崎 尚, 他
  • Organizer: BMB2007第30回日本分子生物学会年会第80回日本生化学会大会合同大会
  • Place of Presentation: パシフィコ横浜ヨコハマグランドインターコンチネンタルホテル(横浜)
• [Presentation] SHPS-1によるToll-like receptorを介したサイトカイン産生の制御 (2007)
  • Author(s): 三宅 敦子, 他
  • Organizer: BMB2007第30回日本分子生物学会年会第80回日本生化学会大会合同大会
  • Place of Presentation: パシフィコ横浜ヨコハマグランドインターコンチネンタルホテル(横浜)
• [Presentation] NKT細胞の活性化と癌転移抑制におけるSHPS-1の役割 (2006)
  • Author(s): 岡上 準、他
  • Organizer: 第65回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(横浜)
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] SHPS-1によるマクロファージ貪食抑制の分子機構:変異型SHPS-1を用いた検討 (2006)
  • Author(s): 池田 洋、他
  • Organizer: 第65回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(横浜)
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Mutational analysis of the mechanism of negative regulation by Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 of phagocytosis in macrophages (2006)
  • Author(s): Ikeda, H., Okazawa, H., Murata, Y., Ohnishi, H., Matozaki, T.
  • Organizer: The 65th annual meeting of the Japanese Cancer Asociation
  • Place of Presentation: Pacifico Yokohama
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Regulation by Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 of α-Galactosylceramide-induced antimetastatic activity and Th1 and Th2 responses of NKT cells (2006)
  • Author(s): Okajo, J., Kaneko, Y., Murata, Y., Okazawa, H., Ohnishi, H., Nojima, Y., Matozaki, T.
  • Organizer: The 65th annual meeting of the Japanese Cancer Asociation
  • Place of Presentation: Pacifico Yokohama
  • Description: 「研究成果報告書概要(欧文)」より