The study about transcriptional regulation and signal transduction of collagen genes in scleroderma fibroblasts

2007 Fiscal Year Final Research Report Summary

• Project/Area Number: 17591161
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Dermatology
• Research Institution: Kumamoto University
• Principal Investigator: IHN Hironobu Kumamoto University, Dept of Dermatol. & Plastic Surg., Professor & Chairman (20282634)
• Project Period (FY): 2005 – 2007
• Keywords: collagen / fibroblastys / TGF-β / seleroderma / transcriptional regulatio / signal transduction

Research Abstract

Excessive extracellular matrix deposition in the skin, lung, and other organs is a hallmark of systemic sclerosis (SSc). Fibroblasts isolated from sclerotic lesions in patients with SSc and cultured in vitro are characterized by increased synthesis of collagen and other extracellular matrix, consistent with the disease phenotype. Thus, cultured scleroderma fibroblasts serve as a principal experimental model for studying the mechanisms involved in extracellular matrix overproduction in SSc. The pathogenesis of SSc is still poorly understood, but increasing evidence suggests that transforming growth factor -β (TGF-β)is a key mediator of tissue fibrosis as a consequence of extracellular matrix accumulation in the pathology of SSc. Our study suggests that autocrine TGF-β signaling induces constitutive phosphorylation of Smad3 and Sp 1, and increased interaction between Smad3 and Sp1 as well as p300 in fibrosis, which causes excessive expression of extracellular matrix proteins. Furthermore, it was shown that overexpression of αvβ5 integrin activates endogenous TGF-β on the cell surface, that activated TGF-β binds to overexpressed TGF-β receptors, and that TGF-β signaling is constitutively activated in fibrosis.

Research Products

• [Journal Article] Autocrine TGF-R signaling in the pathogenesis of systemic sclerosis (2008)
  • Author(s): Ihn H.
  • Journal Title: J Dermatol Sci 49 Pages: 103-113
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Autocrine TGF-β signaling in the pathogenesis of systemic sclerosis (2008)
  • Author(s): Ihn, H
  • Journal Title: J Dermatol Sci 49 Pages: 103-113
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] High-dose intravenous immune globulin infusion as treatment for diffuse scleroderma (2007)
  • Author(s): Ihn H, Mimura Y, Yazawa N, Jinnin M, Asano Y, Yamane K, Tamaki K.
  • Journal Title: Br J Dermatol 156 Pages: 1058-1060
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] p38 MAP kinase inhibitors in dermatology (2007)
  • Author(s): Ihn H.
  • Journal Title: Eap Rev Dermatol 2 Pages: 403-407
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Epidermal growth factor up-regulates transforming growth factor -βreceptor II in human dermal fibroblasts via the p38 mitogen-activated protein kinase pathway (2007)
  • Author(s): Yamane, K., Asano, Y., Tamaki, K., Ihn, H
  • Journal Title: Biochem Biophys Res Commun 352 Pages: 69-77
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of the constitutive complex formation of c-Ski/SnoN with Smads in the impaired negative feedback regulation of transforming growth factor-β signaling in scleroderma fibroblasts (2007)
  • Author(s): Jinnin, M., Ihn, H., Mimura, Y., Asano, Y., Tamaki, K
  • Journal Title: Arthritis Rheum 56 Pages: 1694-1705
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Constitutive phosphorylated Smad3 interactes with Sp l and p300/CBP in scleroderma fibroblasts (2006)
  • Author(s): Ihn H, Yamane K, Asano Y, Jinnin M, Tamaki K.
  • Journal Title: Rheumatology 45 Pages: 157-165
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Platelet derived growth factor induced tenascin-C transcription is phosphoinositide 3-kinase/ Akt -dependent and mediated by Ets family tra nscription factors (2006)
  • Author(s): Jinnin, M., Ihn, H., Asano, Y., Yamane, K., Trojanowska, M., Tamaki, K
  • Journal Title: J Cell Physiol 206 Pages: 718-727
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Constitutive phosphorylated Smad3 interactes with Spl and p300/CBP in scleroderma fibroblasts (2006)
  • Author(s): Ihn, H., Yamane, K., Asano, Y., Jinnin, M., Tamaki, K
  • Journal Title: Rheumatology 45 Pages: 157-165
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-β1-indueed extracellular matrix expression (2006)
  • Author(s): Jinnin, M., Ihn, H., Tamaki, K
  • Journal Title: Mol Pharmacol 69 Pages: 597-607
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Increased expression of intgrin αvβ5 induces the myofibroblastic differentiation of dermal fibroblasts. (2006)
  • Author(s): Asano, Y., Ihn, H., Yamane, K., Jinnin, M., Tamaki, K
  • Journal Title: Am J Pathol 168 Pages: 499-510
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Upregulation of tenascin-C expression by IL- 13 in human dermal fibroblasts via the phosphoinositide 3-kinase/ Akt and protein kinase C signaling pathways (2006)
  • Author(s): Jinnin, M., Ihn, H., Asano, Y., Yamane, K., Trojanowska, M., Tamaki, K
  • Journal Title: J Invest Dermatol 126 Pages: 551-560
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Potential regulatory elements of the constitutively up-regulated α2(I) collagen gene in scleroderma dermal fibroblasts (2006)
  • Author(s): Jinnin, M., Ihn, H., Mimura, Y., Asano, Y., Tamaki, K
  • Journal Title: Biochem Biophys Res Commun 343 Pages: 904-909
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Epidermal growth factor affects the synthesis and degradation of type I collagen in cultured human dermal fibroblasts (2006)
  • Author(s): Mimura, Y., Ihn, H., Jinnin, M., Asano, Y., Yamane, K., Tamaki, K
  • Journal Title: Matrix Biology 25 Pages: 202-212
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of αvβ5 intgrin in the establishment of autocrine TGF-β signaling in dermal fibroblasts derived from localized scleroderma (2006)
  • Author(s): Asano, Y., Ihn, H., Jinnin, M., Mimura, Y., Tamaki, K
  • Journal Title: J Invest Dermatol 126 Pages: 1761-1769
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Scleroderma,fibroblasts,signaling,and excessive extracellular matrix (2005)
  • Author(s): Ihn H.
  • Journal Title: Curr Rheumatol Rep 7 Pages: 156-162
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Increased phosphorylation and activation of mitogen-activated protein kinase p38 in scleroderma fibroblasts (2005)
  • Author(s): Ihn H, Yamane K, Tamaki K.
  • Journal Title: J Invest Dermatol 125 Pages: 247-255
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Regulation of fibrogenic/fibrolytic genes by platelet derived growth factor C, a novel growth factor, in human dermal fibroblasts (2005)
  • Author(s): Jinnin, M., Ihn, H., Mimura, Y., Asano, Y., Yamane, K., Tamaki, K
  • Journal Title: J Cell Physiol 202 Pages: 510-517
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cell type-specific regulation of the TGF-β-responsive α2(I) collagen gene by CpG methylation (2005)
  • Author(s): Yamane, K., Suzuki, H., Ihn, H., Kato, M., Yoshikawa, H., Tamaki, K
  • Journal Title: J Cell Physiol 202 Pages: 822-830
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effects of hepatocyte growth factor on the expression of type I collagen and matrix metalloprotcinase-1 in normal and scleroderma dermal fibroblasts. (2005)
  • Author(s): Jinnin, M., Ihn, H., Mimura, Y., Asano, Y., Yamane, K., Taraaki, K
  • Journal Title: J Invest Dermatol 124 Pages: 324-330
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] α2(I) collagen gene regulation by protein kinase C signaling in human dermal fibroblasts (2005)
  • Author(s): Jinnin, M., Ihn, H., Yamane, K., Mimura, Y., Asano, Y., Tamaki, K
  • Journal Title: Nucleic Acids Res 33 Pages: 1337-1351
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Scleroderma, fibroblasCs, signaling, and excessive extracellular matrix. (2005)
  • Author(s): Ihn, H
  • Journal Title: Curr Rheumatol Rep 7 Pages: 156-162
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Differential effects of the immunosuppressant FK506 on human α2(I) collagen gene expression and transforming growth factor β signaling in normal and scleroderma fibroblasts (2005)
  • Author(s): Asano, Y., Ihn, H., Yamane, K., Jinnin, M., Mimura, Y., Tamaki, K
  • Journal Title: Arthritis Rheum 52 Pages: 1237-1247
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Constitutive thrombospondin-1 overexpression contributes to autocrine transforming growth factor-β signaling in cultured scleroderma fibroblasts (2005)
  • Author(s): Mimura, Y., Ihn, H., Jinnin, M., Asano, Y., Yamane, K., Tamaki, K
  • Journal Title: Am J Pathol 166 Pages: 1451-1463
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Constitutive phosphorylation of focal adhesion kinase is involved in the myofibroblast differentiation of scleroderma fibroblasts (2005)
  • Author(s): Mimura, Y., Ihn, H., Jinnin, M., Asano, Y., Yamane, K., Tamaki, K
  • Journal Title: J Invest Dermatol 124 Pages: 886-892
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Matrix metalloproteinase-1 up-regulation by hepatocyte growth factor in human dermal fibroblasts via ERK signaling pathway involves Etsl and Flil (2005)
  • Author(s): Jinnin, M., Ihn, H., Mimura, Y., Asano, Y., Yamane, K., Tamaki, K
  • Journal Title: Nucleic Acids Res 33 Pages: 3540-3549
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Increased phosphorylation and activation of mitogen-activated protein kinase p38 in scleroderma fibroblasts (2005)
  • Author(s): Ihn, H., Yamane, K., Tamaki, K
  • Journal Title: J Invest Dermatol 125 Pages: 247-255
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement ofαVβ35 intgrin-mediated activation of latent transforming growth factor β in autocrine transforming growth factor β signaling in systemic sclerosis fibroblasts (2005)
  • Author(s): Asano, Y., Ihn, H., Yamane, K., Jinnin, M., Mimura, Y., Tamaki, K
  • Journal Title: Arthritis Rheurn 52 Pages: 2897-2905
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Increased expression of integrin αvβ3 contributes to the establishment of autocrine TGF-β signaling in scleroderma dermal fibroblasts (2005)
  • Author(s): Asano, Y., Ihn, H., Yamane, K., Jinnin, M., Mimura, Y., Tamaki, K
  • Journal Title: J Immunol 175 Pages: 7708-7718
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] A case report of epidermolysis bullosa acquisita (2008)
  • Author(s): Sakai, K., Nagata, T., Inoue, Y., Hashimoto, T., Ihn, H
  • Organizer: Post IID 2008 Satellite International Meeting on Autoimmune Bullous Diseases
  • Place of Presentation: 大津
  • Year and Date: 20080517-19
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Molecular analysis of the genetic aberrations in derraatofib rosa rcom ap rotu bera ns (2008)
  • Author(s): Chikwanha, FC, Wakasugi, S., Ihn, H
  • Organizer: International Investigative Dermatology 2008
  • Place of Presentation: Kyoto
  • Year and Date: 20080514-17
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Identification and characterization of a novel centrosomal protein (2008)
  • Author(s): Makino, K., Ihn, H
  • Organizer: International Investigative Dermatology 2008
  • Place of Presentation: Kyoto
  • Year and Date: 20080514-17
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Effective imm unotherapy with a-GalCer-loaded embryonic stem cell-derived dendric cells expressing multiple antigens against B16 melanoma (2008)
  • Author(s): Fukushima, S., Ihn, H., Nishimura, Y., Senju, S
  • Organizer: International Investigative Dermatology 2008
  • Place of Presentation: Kyoto
  • Year and Date: 20080514-17
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Basic fibroblast growth factor stimulates the proliferation of dermal fibroblasts via activation of ERKl/2-dependent pathway (2008)
  • Author(s): Makino, T., Johno, T., Zhang, X., Wakasugi, S., Inoue, Y., Ihn, H
  • Organizer: International Investigative Dermatology 2008
  • Place of Presentation: Kyoto
  • Year and Date: 20080514-17
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Lupus erythematosus profundus clinical and pathological features of 12cases (2008)
  • Author(s): Miyashita, A., Jono, T., Makino, T., Yoshino, Y., Hironobu, Ihn
  • Organizer: 2nd International Conference on Cutaneous Lupus Erythematosus
  • Year and Date: 20080511-13
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] TGf-β autocrine systems in scleroderma fibroblasts (2007)
  • Author(s): Hironobu, Ihn
  • Organizer: Professor E. Carwile Memorial International Workshop on Scleroderma(Tokyo) Invited lecture
  • Year and Date: 20070518-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] The efficacy of systemic steroid therapy for systemic sclerosis : Improvement of total skin thickness score and joint involvement (2007)
  • Author(s): Takamitsu, Johno, Takamitsu, Makino, Hironobu, Ihn
  • Organizer: Professor E. Carwile Memorial International Workshop on Scleroderma
  • Place of Presentation: Tokyo
  • Year and Date: 20070518-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Clinical features of scleroderma patients with contracture of phalanges (2007)
  • Author(s): Ryuichi, Ashida, Hironobu, Ihn, Yoshihiro, Mimura, Masatoshi, Jinnin, Yoshihide, Asano, Masahide, Kubo, Kunihiko, Tamaki
  • Organizer: Professor E. Carwile Memorial International Workshop on Scleroderma
  • Place of Presentation: Tokyo
  • Year and Date: 20070518-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] A case of systemic sclerosis without serum antinuclear antibodies (2007)
  • Author(s): Takamitsu, Makino, Keishi, Maruo, Hironobu, Ihn
  • Organizer: Professor E. Carwile Memorial International Workshop on Scleroderma
  • Place of Presentation: Tokyo
  • Year and Date: 20070518-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Accuracy and clinical utility of a commercial ELISA kit for detection of anti-RNA polymerase III antibody (2007)
  • Author(s): Takashi, Satoh, Masataka, Kuwana, Osamu, Ishikawa, Hironobu, Ihn, Hirahito, Endo, Yasushi, Kawaguchi, Ttetsuo, Sasaki, Daisuke, Goto, Kazuo, Takahashi, Yuki, Takahashi, Yoshikata, Misaki, Tsuneyo, Mimori, Yoshinao, Muro, Norihito, Yazawa, Shinichi, Sato, Kazuhiko, Takehara
  • Organizer: Professor E. Carwile Memorial International Workshop on Scleroderma
  • Place of Presentation: Tokyo
  • Year and Date: 20070518-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] A case of linear scleroderma accompanied with endocranial abnormality (2007)
  • Author(s): Manabu, Tomita, Zenshiro, Tamaki, Yoshihiro, Mimura, Masatoshi, Jinnin, Norihito, Yazawa, Masahide, Kubo, Hironobu, Ihn, Kunihiko, Tamaki
  • Organizer: Professor E. Carwile Memorial International Workshop on Scleroderma
  • Place of Presentation: Tokyo
  • Year and Date: 20070518-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Identification and characerization of novel centrosomal proteins (2007)
  • Author(s): Makino, K., Umeda, K., Uezu, A., Sakamoto, T., Ihn, H., Nakanishi, H
  • Organizer: The 32nd Annual Meeting of The Japanese Society for Investigative Dermatology
  • Year and Date: 20070418-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Embryonic stem cell-derived dendric cells expressing glypican-3, an oncofetal antigen, induced protective immunity against mouse melanoma (2007)
  • Author(s): Fukushima, S., Motomura, Y., Senju, S., Nakatsura, T., Nishimura, Y., Ihn, H
  • Organizer: The 32nd Annual Meeting of The Japanese Society for Investigative Dermatology
  • Year and Date: 20070418-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] The expression levels of thrombospondin-1 in dermatofibroma and dermatofibrosarcoma protuberans (2005)
  • Author(s): Maekawa, T., Jinnin, M., Ihn, H., Tamaki, K
  • Organizer: The 66th Meeting of the Society for Investigative Dermatology
  • Place of Presentation: St. Louis, MO
  • Year and Date: 20050504-07
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] α2(I) collagen gene regulation by protein kinase C signaling in human dermal fibroblasts (2005)
  • Author(s): Jinnin, M., Ihn, H., Yamano, K., Mimura, Y., Asano, Y., Tamaki, K
  • Organizer: The 66th Meeting of the Society for Investigative Dermatology
  • Place of Presentation: St. Louis, MO
  • Year and Date: 20050504-07
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Molecular mechanism of fibrosis" JSID Award Lecture (2005)
  • Author(s): Hironobu, Ihn
  • Organizer: The 30th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Yokohama
  • Year and Date: 2005-04-21
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Differential effects of FK506 on human α2(I) collagen gene expression and TGF-β signaling between normal and scleroderma fibroblasts (2005)
  • Author(s): Yoshihide, Asano, Hironobu, Ihn, Kenichi, Yamane, Masatoshi, Jinnin, Yoshihiro, Mimura, Kunihiko, Tamaki
  • Organizer: The 30th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Yokohama
  • Year and Date: 2005-04-21
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] The expression levels of TGF-β receptors in dermatofibroma and dermatofibrosarooma protuberans (2005)
  • Author(s): Masahide, Kubo, Hironobu, Ihn, Kenichi, Yamane, Kunihiko, Tamaki
  • Organizer: The 30th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Yokohama
  • Year and Date: 2005-04-21
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Contitutive phosphorylation of focal adhesion kinase is involved in the myofibroblast differentiation of scleroderma fibroblasts (2005)
  • Author(s): Yoshihiro, Mimura, Hironobu, Ihn, Masatoshi, Jinnin, Yoshihide, Asano, Kenichi, Yamane, Kunihiko, Tamaki
  • Organizer: The 30th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: Yokohama
  • Year and Date: 2005-04-21
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] α2(I) collagen gene regulation by protein kinase C signaling in human dermal fibrobiasts (2005)
  • Author(s): Masatoshi, Jinnin, Hironobu, Ihn, Yoshihiro, Mimura, Yoshihide, Aaano, Kenichi, Yamane, Kunihiko, Tamaki
  • Organizer: The 30th Annual Meeting of the Japanese Society for Investi gative Dermatology
  • Place of Presentation: Yokohama
  • Year and Date: 2005-04-21
  • Description: 「研究成果報告書概要(欧文)」より