Role of signal transduction pathway of Bcl-3 and IkBNA in the pathogenesis of psoriasis

• Project/Area Number: 21390325
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Dermatology
• Research Institution: Ehime University
• Principal Investigator: HASHIMOTO Koji 愛媛大学, 先端研究・学術推進機構学術企画室, 特命教授 (00110784)
• Co-Investigator(Kenkyū-buntansha): MURAKAMI Shinji 愛媛大学, 大学院医学系研究科, 准教授 (50175626)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2011: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2010: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2009: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: 尋常性乾癬 / シグナル伝達 / 培養角化細胞 / NFkB / Bcl-3 / IkBNS / IkBNF / IkBNS欠損マウス / STAT3 / Bc1-3

Research Abstract

In order to clarify the role of NF-kB in the pathogenesis of psoriasis, we examined whether pathological change of psoriasis was induced in IkBNS deficient mice. We also clarified the function of Bcl-3 in cultured epidermal keratinocytes. Although the IkBNS deficient mice did not spontaneously generate psoriatic skin phenotype, the psoriasis pathological change was induced by the wound stimulus and the TPA treatment. IL-22-induced psoriasis-related genes were suppressed by the pretreatment of Bcl-3 suppression. On the other hand, overexpression of Bcl-3 induced psoriasis-related gene expression. Furthermore, Bcl-3 was strongly detected psoriatic skin. In conclusion, NFkB and Bcl-3 play important roles in the pathogenesis of psoriasis.

Research Products

• [Journal Article] Targeted overexpression of Angptl6/angiopoietin-related growth factor in the skin promotes angiogenesis and lymphatic vessel enlargement in response to ultraviolet B (2012)
  • Author(s): Okazaki H, Hirakawa S, Shudou M, Nakaoka Y, Shirakata Y, Miyata K, Oike Y, Hashimoto K, Sayama K
  • Journal Title: J Dermatol Volume: 39 Pages: 366-74
  • NAID: 10031184909
  • Peer Reviewed
• [Journal Article] Interactions between myofibroblast differentiation and epidermogenesis in constructing human living skin equivalents (2012)
  • Author(s): Yang L, Hashimoto K, Tohyama M, Okazaki H, Dai X, Hanakawa Y, Sayama K, Shirakata Y
  • Journal Title: J Dermatol Sci Volume: 65 Pages: 50-7
  • Peer Reviewed
• [Journal Article] Epidermogenesis in a skin wound deep through the basement membrane contributes to scar formation (2012)
  • Author(s): Yang L, Hashimoto K, Shirakata Y
  • Journal Title: Dermatol Sci Volume: 65 Pages: 224-226
  • Peer Reviewed
• [Journal Article] Cell surface-annexins regulate ADAM-mediated ectodomain shedding of proamphiregulin (2012)
  • Author(s): Nakayama H, Fukuda S, Inoue H, Nishida-Fukuda H, Shirakata Y, Hashimoto K, Higashiyama S
  • Journal Title: Mol Biol Cell Volume: (in press)
  • Peer Reviewed
• [Journal Article] Hair-inducing ability of human dermal papilla cells cultured under Wnt/β-catenin signalling activation (2012)
  • Author(s): Soma T, Fujiwara S, Shirakata Y, Hashimoto K, Kishimoto J
  • Journal Title: Exp Dermatol Volume: 21 Pages: 307-9
  • Peer Reviewed
• [Journal Article] Pathogenic Anti-Desmoglein 3 mAbs Cloned from a Paraneoplastic Pemphigus Patient by Phage Display (2012)
  • Author(s): Saleh MA, Ishii K, Yamagami J, Shirakata Y, Hashimoto K, Amagai M
  • Journal Title: J Invest Dermatol Volume: 132 Pages: 1141-8
  • Peer Reviewed
• [Journal Article] Possible involvement of CD14+ CD16+ monocyte lineage cells in the epidermal damage of Stevens-Johnson syndrome and toxic epidermal necrolysis (2012)
  • Author(s): Tohyama M, Watanabe H, Murakami S, Shirakata Y, Sayama K, Iijima M, Hashimoto K
  • Journal Title: Br J Dermatol Volume: 166 Pages: 322-30
  • Peer Reviewed
• [Journal Article] Possible involvement of CD146+ CD16+ monocyte lineage cells in the epidermal damage of Stevens-Johnson syndrome and toxic epidermal necrolysis (2012)
  • Author(s): Tohyama M, et al
  • Journal Title: Br J Dermatol Volume: 166 Issue: 2 Pages: 322-30
  • DOI: 10.1111/j.1365-2133.2011.10649.x
  • Peer Reviewed
• [Journal Article] Targeted overexpression of Angpt16/angiopoietin-related growth factor in the skin promotes angiogenesis and lymphatic vessel enlargement in response to ultraviolet B (2012)
  • Author(s): Okazaki H, et al
  • Journal Title: J Dermatol Volume: 39 Issue: 4 Pages: 366-74
  • DOI: 10.1111/j.1346-8138.2011.01396.x
  • Peer Reviewed
• [Journal Article] Epidermogenesis in a skin wound deep through the basement membrane contributes to scar formation (2012)
  • Author(s): Yang L, et al
  • Journal Title: J Dermatol Sci Volume: 65 Issue: 3 Pages: 224-226
  • DOI: 10.1016/j.jdermsci.2011.10.006
  • Peer Reviewed
• [Journal Article] Cell surface-annexins regulate ADAM-mediated ectodomain shedding of proamphiregulin (2012)
  • Author(s): Nakayama H
  • Journal Title: Mol Biol Cell Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Development of NC1 and NC2 domains of Type VII collagen ELISA for the diagnosis and analysis of time course of epidermolysis bullosa acquisita patients (2011)
  • Author(s): Saleh MA, Ishii K, Kim Y, Murakami A, Ishii N, Hashimoto T, Schmidt E, Zillikens D, Shirakata Y, Hashimoto K, Kitajima Y, Amagai M
  • Journal Title: J Dermatol Sci Volume: 62 Pages: 169-75
  • NAID: 10030891389
  • Peer Reviewed
• [Journal Article] Genome-wide association study identifies HLA-A* 3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population (2011)
  • Author(s): Ozeki T, Mushiroda T, Yowang A, Takahashi A, Kubo M, Shirakata Y, Ikezawa Z, Iijima M, Shiohara T, Hashimoto K, Kamatani N, Nakamura Y
  • Journal Title: Hum Mol Genet Volume: 20 Pages: 1034-41
  • Peer Reviewed
• [Journal Article] Mite allergen is a danger signal for the skin via activation of inflammasome in keratinocytes (2011)
  • Author(s): Dai X, Sayama K, Tohyama M, Shirakata Y, Hanakawa Y, Tokumaru S, Yang L, Hirakawa S, Hashimoto K
  • Journal Title: J Allergy Clin Immunol Volume: 127 Pages: 806-814
  • Peer Reviewed
• [Journal Article] Nuclear translocation of phosphorylated STAT3 regulates VEGF-A-induced lymphatic endothelial cell migration and tube formation (2011)
  • Author(s): Okazaki H, Tokumaru S, Hanakawa Y, Shiraishi K, Shirakata Y, Dai X, Yang L, Tohyama M, Hashimoto K, Sayama K.
  • Journal Title: Biochem Biophys Res Commun Volume: 412 Pages: 441-5
  • Peer Reviewed
• [Journal Article] Hair-inducing ability of human dermal papilla cells cultured under Wnt/β-catenin signalling activation (2011)
  • Author(s): Soma T, et al
  • Journal Title: Exp Dermatol Volume: 21 Issue: 4 Pages: 307-9
  • DOI: 10.1111/j.1600-0625.2012.01458.x
  • Peer Reviewed
• [Journal Article] Genome-wide association study identifies HLA-A^*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population (2011)
  • Author(s): Ozeki T, et al
  • Journal Title: Hum Mol Genet Volume: 20 Issue: 5 Pages: 1034-41
  • DOI: 10.1093/hmg/ddq537
  • Peer Reviewed
• [Journal Article] Auto-and cross-induction by betacellulininepidermal keratinocytes (2010)
  • Author(s): Shirakata Y, Tokumaru S, Sayama K, Hashimoto K
  • Journal Title: J DermatolSci Volume: 162 Pages: 162-4
  • Peer Reviewed
• [Journal Article] Inflammatory mediator TAK1 regulatesrashes hair follicle morphogenesis and anagen induction shown by using keratinocyte-specific TAK1-deficient mice (2010)
  • Author(s): Sayama K, Kajiya K, Sugawara K, Sato S, Hirakawa S, Shirakata Y, Hanakawa Y, Dai X, Ishimatsu-Tsuji Y, Metzger D, Chambon P, Akira S, Paus R, Kishimoto J, Hashimoto K
  • Journal Title: PLoS One Volume: 5 Pages: 11275-11275
  • Peer Reviewed
• [Journal Article] E2 Polyubiquitin-conjugating enzyme Ubc13 in keratinocytes is essential for epidermal integrity (2010)
  • Author(s): Sayama K, Yamamoto M, ShirakataY, Hirakawa S, Dai X, Tohyama M, Tokumaru S, Shin MS, Sakurai H, Akira S, Hashimoto K
  • Journal Title: J Biol Chem Volume: 285 Pages: 30042-9
  • Peer Reviewed
• [Journal Article] PPARγmediates innate immunity by regulating the 1α, 25-dihydroxyvitamin D3 induced hBD-3 and cathelicidin in human keratinocytes (2010)
  • Author(s): Dai X, Sayama K, Tohyama M, Shirakata Y, Hanakawa Y, Tokumaru S, Yang L, Hirakawa S, Hashimoto K
  • Journal Title: J Dermatol Sci Volume: 60 Pages: 179-86
  • Peer Reviewed
• [Journal Article] Occupational trichloroethylene hypersensitivity syndrome with human herpesvirus-6 and cytomegalovirus reactivation (2010)
  • Author(s): Watanabe H, Tohyama M, Komijima M, Nakajima T, Yohida T, Hashimoto K, and Iijima M
  • Journal Title: Dermatology Volume: 221 Pages: 408-410
  • Peer Reviewed
• [Journal Article] Fluctuation of blood and skin plasmacytoid dendritic cells in drug-induced hypersensitivity syndrome (2010)
  • Author(s): Sugita K, Tohyama M, Watanabe H, Otsuka A, Nakajima S, Iijima M, Hashimoto K, Tokura Y, Miyachi Y, Kabashima K
  • Journal Title: J Allergy Clin Immunol Volume: 126 Pages: 408-410
  • Peer Reviewed
• [Journal Article] Auto- and cross-induction by betacellulin in epidermal keratinocytes. (2010)
  • Author(s): Shirakata Y, Tokumaru S, Sayama K, Hashimoto K
  • Journal Title: Journal of Dermatological Science Volume: 58 Pages: 162-4
  • NAID: 10027400978
  • Peer Reviewed
• [Journal Article] Inflammatory mediator TAK1 regulates hair follicle morphogenesis and anagen induction shown by using keratinocyte-specific TAK1-deficient mice. (2010)
  • Author(s): Sayama K, Kajiya K, Sugawara K, Sato S, Hirakawa S, Shirakata Y, Hanakawa Y, Dai X, Ishimatsu-Tsuji Y, Metzger D, Chambon P, Akira S, Paus R, Kishimoto J, Hashimoto K
  • Journal Title: PLoS One Volume: 5
  • Peer Reviewed
• [Journal Article] E2 Polyubiquitin-conjugating enzyme Ubc13 in keratinocytes is essential for epidermal integrity. (2010)
  • Author(s): Sayama K, Yamamoto M, Shirakata Y, Hanakawa Y, Hirakawa S, Dai X, Tohyama M, Tokumaru S, Shin MS, Sakurai H, Akira S, Hashimoto K
  • Journal Title: Journal of Biological Chemistry Volume: 285 Pages: 30042-9
  • Peer Reviewed
• [Journal Article] PPARγ mediates innate immunity by regulating the 1α, 25-dihydroxyvitamin D3 induced hBD-3 and cathelicidin in human keratinocytes. (2010)
  • Author(s): Dai X, Sayama K, Tohyama M, Shirakata Y, Hanakawa Y, Tokumaru S, Yang L, Hirakawa S, Hashimoto K
  • Journal Title: Journal of Dermatological Science Volume: 60 Pages: 179-86
  • NAID: 10027841095
  • Peer Reviewed
• [Journal Article] Occupational trichloroethylene hypersensitivity syndrome with human herpesvirus-6 and cytomegalovirus reactivation (2010)
  • Author(s): Watanabe H, Tohyama M, Komijima M, Nakajima T, Yohida T, Hashimoto K, Iijima M
  • Journal Title: Dermatology Volume: 221 Pages: 17-22
  • Peer Reviewed
• [Journal Article] Fluctuation of blood and skin plasmacytoid dendritic cells in drug-induced hypersensitivity syndrome. (2010)
  • Author(s): Sugita K, Tohyama M, Watanabe H, Otsuka A, Nakajima S, Iijima M, Hashimoto K, Tokura Y, Miyachi Y, Kabashima K.
  • Journal Title: J Allergy Clin Immunol Volume: 126 Pages: 408-410
  • Peer Reviewed
• [Journal Article] Diagnosis and treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis with ocular complications (2009)
  • Author(s): Sotozono C, Ueta M, Koizumi N, Inatomi T, Shirakata Y, Ikezawa Z, HashimotoK, Kinoshita S
  • Journal Title: Ophthalmology Volume: 116 Pages: 685-90
  • Peer Reviewed
• [Journal Article] The influence of hepatic damage on serum soluble Fas ligand levels of patients with drug rashes (2009)
  • Author(s): Tohyama M, Shirakata Y, Sayama K, Hashimoto K
  • Journal Title: J Allergy Clin Immunol Volume: 123 Pages: 971-2
  • Peer Reviewed
• [Journal Article] Alteration of TLR3 pathways by glucocorticoids may be responsible for immunosusceptibility of human corneal epithelial cells to viral infections (2009)
  • Author(s): Hara Y, Shiraishi A, Kobayashi T, Kadota Y, Shirakata Y, Hashimoto K, Ohashi Y
  • Journal Title: Mol Vis Volume: 15 Pages: 937-48
  • Peer Reviewed
• [Journal Article] IL-17 and IL-22 mediate IL-20 subfamily cytokine production in cultured keratinocytes via increased IL-22 receptor expression (2009)
  • Author(s): Tohyama M, Hanakawa Y, Shirakata Y, Dai X, Yang L, Hirakawa S, Tokumaru S, Okazaki H, Sayama K, Hashimoto K
  • Journal Title: Eur J Immunol Volume: 39 Pages: 2279-88
  • Peer Reviewed
• [Journal Article] Living Skin Equivalents Constructed Using Human Amnions as a Matrix (2009)
  • Author(s): Yang L, Shirakata Y, Tokumaru S, Xiuju D, Tohyama M, Hanakawa Y, Hirakawa S, Sayama K, Hashimoto K
  • Journal Title: J Dermatol Sci Volume: 56 Pages: 188-95
  • NAID: 10027398843
  • Peer Reviewed
• [Journal Article] Nodal Lymphangiogenesis and Metastasis : Role of Tumor-Induced Lymphatic Vessel Activation in Extramammary Paget's Disease (2009)
  • Author(s): Hirakawa S, Detmar M, Kerjaschki D, Nagamatsu S, Matsuo K, Tanemura A, Kamata N, Higashikawa K, Okazaki H, Kameda K, Nishida-Fukuda H, Mori H, Hanakawa Y, Sayama K, Shirakata Y, Tohyama M, Tokumaru S, Katayama I, Hashimoto K
  • Journal Title: Am J Pathol Volume: 175 Pages: 2235-48
  • Peer Reviewed
• [Journal Article] Diagnosis and treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis with ocular complications (2009)
  • Author(s): Sotozono C, Ueta M, Koizumi N, Inatomi T, Shirakata Y, Ikezawa Z, Hashimoto K, Kinoshita S.
  • Journal Title: Ophthalmology 116 Pages: 685-90
  • Peer Reviewed
• [Journal Article] The influence of hepatic damage on serum soluble Fas ligand levels of patients with drug rashes (2009)
  • Author(s): Tohyama M, Shirakata Y, Sayama K, Hashimoto K
  • Journal Title: J Allergy Clin Immunol 123 Pages: 971-2
  • Peer Reviewed
• [Journal Article] Alteration of TLR3 pathways by glucocorticoids may be responsible for immunosusceptibility of human corneal epithelial cells to viral infections (2009)
  • Author(s): Hara Y, Shiraishi A, Kobayashi T, Kadota Y, Shirakata Y, Hashimoto K, Ohashi Y
  • Journal Title: Mol Vis 15 Pages: 937-48
  • Peer Reviewed
• [Journal Article] IL-17 and IL-22 mediate IL-20 subfamily cytokine production in cultured keratinocytes via increased IL-22 receptor expression (2009)
  • Author(s): Tohyama M, Hanakawa Y, Shirakata Y, Dai X, Yang L, Hirakawa S, Tokumaru S, Okazaki H, Sayama K, Hashimoto K
  • Journal Title: Eur J Immunol 39 Pages: 2279-88
  • Peer Reviewed
• [Journal Article] Living Skin Equivalents Constructed Using Human Amnions as a Matrix (2009)
  • Author(s): Yang L, Shirakata Y, Tokumaru S, Xiuju D, Tohyama M, Hanakawa Y, Hirakawa S, Sayama K, Hashimoto K
  • Journal Title: J Dermatol Sci 56 Pages: 188-95
  • NAID: 10027398843
  • Peer Reviewed
• [Journal Article] Nodal Lymphangiogenesis and Metastasis : Role of Tumor-Induced Lymphatic Vessel Activation in Extramammary Paget's Disease (2009)
  • Author(s): Hirakawa S, Hashimoto K, 他
  • Journal Title: Am J Pathol 175 Pages: 2235-48
  • Peer Reviewed
• [Presentation] Overlap between the Drug-induced hypersensitivity syndrome and the Stevens Johnson Syndrome (2010)
  • Author(s): Hashimoto K
  • Organizer: 4^<th> International Drug Hypersensitivity Meeting
  • Year and Date: 2010-06-10
• [Presentation] Deletion of SOCS3 in the epidermis causes impaired skin wound healing in vivo (2010)
  • Author(s): Shirakata Y, Yang L, Tsuda T, Tohyama M, Miyawaki S, Kameda K, Sayama K, Yoshimura A, Hashimoto K
  • Organizer: The 40^h Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: Helsinki, Finland
• [Presentation] Interferon alpha enhances IL-22 receptor expression on epidermal keratinocytes (2010)
  • Author(s): Tohyama M, Yang L, Tsuda T, Miyawaki S, Shirakata Y, Sayama K, Hashimoto K
  • Organizer: The 40^h Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: Helsinki, Finland
• [Presentation] Mite allergen is a danger signal for the skin (2010)
  • Author(s): Sayama K, Dai X, Shirakata Y, Tohyama M, Miyawaki S, Hirakawa S, Hashimoto K
  • Organizer: The 40^h Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: Helsinki, Finland
• [Presentation] Successful treatment of severe pemphigus vulgaris with high-dose intravenous immunoglobulin (2010)
  • Author(s): Shirakata Y, Ishikawa M, Murakami S, Hashimoto K
  • Organizer: 9^<th> Meeting of the German-Japanese Society of Dermatology
  • Place of Presentation: Weimar, Germany
• [Presentation] Successful treatment of severe pemphigus vulgaris with high-dose intravenous immunoglobulin. (2010)
  • Author(s): Shirakata Y, Ishikawa M, Murakami S, Hashimoto K
  • Organizer: 9^<th> Meeting of the German-Japanese Society of Dermatology
  • Place of Presentation: Weimar, Germany
• [Presentation] Deletion of SOCS3 in the epidermis causes impaired skin wound healing in vivo. (2010)
  • Author(s): Shirakata Y, Yang L, Tsuda T, Tohyama M, Miyawaki S, Kameda K, Sayama K, Yoshimura A, Hashimoto K
  • Organizer: The 40^h Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: Helsinki, Finland
• [Presentation] Simple method of constructing living skin equivalent using human amnion as dermal matrix (2009)
  • Author(s): Shirakata Y, Yang L, Sayama K, and Hashimoto K
  • Organizer: The 39^<th> Annual Meeting of European Society for Dermatological Research
  • Place of Presentation: Budapest, Hungary
• [Presentation] Development of a new skin equivalent using de-epithelialized amnion membrane (2009)
  • Author(s): Shirakata Y and Hashimoto K
  • Organizer: The 4^<th> Joint Meeting of Japanese Dermatological Association and Australasian College of Dermatologists
  • Place of Presentation: Sapporo, Japan
• [Presentation] Lymph node lymphangiogenesis-a new concept in cancer metastasis (2009)
  • Author(s): Hirakawa S, and Hashimoto K
  • Organizer: Symposium in 7^<th> World Congress on Melanoma and 5^<th> Congress of the European Association of Dermato-Oncology(EADO)
  • Place of Presentation: Vienna, Austria
• [Presentation] Inflammatory mediator TAK1 regulates hair follicle cycling (2009)
  • Author(s): Sayama K, Shirakata Y, Ishimatsu-Tsuji Y, Kajiya K, Hirakawa S, Sugawara K, Chambon P, Akira S, Paus R, Kishimoto J, and Hashimoto K
  • Organizer: The 69^<th> Annual Meeting of Society for Investigative Dermatology
  • Place of Presentation: Montreal, Canada
• [Presentation] Development of a new skin equivalent using de-epithelialized amnion membrane (2009)
  • Author(s): Shirakata Y, Hashimoto K
  • Organizer: The 4^<th> Joint Meeting of Japanese Dermatological Association and Australasian College of Dermatologists
  • Place of Presentation: Sapporo