Induction of polyclonal IgE response by LPS-stimulated basophils

• Project/Area Number: 17390145
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: Hyogo College of Medicine
• Principal Investigator: NAKANISHI Kenji Hyogo College of Medicine, Faculty of Medicine, Professor (60172350)
• Co-Investigator(Kenkyū-buntansha): YOSHIMOTO Tomohiro Hyogo College of Medicine, Faculty of Medicine, Associate Professor (60241171) ; TSUTSUI Hiroko Hyogo College of Medicine, Faculty of Medicine, Professor (40236914)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥15,210,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥810,000); Fiscal Year 2007: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2006: ¥4,200,000 (Direct Cost: ¥4,200,000); Fiscal Year 2005: ¥7,500,000 (Direct Cost: ¥7,500,000)
• Keywords: basophils / TLR / IL-18 / IL-33 / APC / Th2 / IgE / 肥満細胞 / TLR4 / LPS / IgE産生 / IL-4

Research Abstract

Basophils and mast cells are important effecter cells in allergic inflammation. Here we investigated whether these cells also induce allergic response by induction of Th2/IgE response. Many microbes express unique pathogen-associated molecular patterns (PAMPs). Upon entry of invading bacteria, DCs recognize them through TLRs and mature to express co-stimulatory molecules CD80 and CD86 and to produce IL-12, IL-18 and other proinflammatory cytokines. Thus, TLR-mediated signaling particularly favors the development and activation of Th1 response. In contrast, the role of innate immune cells in the development of Th2 response is poorly understood. Since basophils produce IL-4 in response to IL-3 plus IL-18, we first tested whether basophils express TLRs and produce IL-4 in response to TLR ligand. We found that both basophils and mast cells express TLR and only basophils produce IL-4 in response to IL-3 plus TLR ligands. We also found both types of cells express IL-18R and IL-33R and only b asophils produce IL-4 in response to IL-18 and/or IL-33 in the presence of IL-3, suggesting the potential of basophils to induce naive CD4+ T cells to develop into Th2 cells by production of IL-4. We next examined whether basophils express molecules that Ag-presenting cells express. Basophils express MHC class II, CD80 and CD86. Naive OVA-specific CD4+ T cells cultured with basophils and OVA peptide with IL-3 but without additional IL-4 developed into cells positive for cytoplasmic IL-4. This capacity of basophils to induce Th2 cells was almost completely abolished by addition of anti-IL-4 antibody, suggesting that IL-4 released from IL-3-stimulated basophils is critically involved in the development of Th2 cells. Then, we added native OVA or DNP-OVA instead of OVA peptide and found that basophile induced the development of OVA-specific naive CD4+ T cells into Th2 cells. Furthermore, basophil pulsed with DNP-OVA in the presence of anti-DNP IgE showed more efficient APC activity than basophils pulsed without anti-DNP IgE, suggesting positive feedback regulation of IgE response by IgE-dependent Ag internalization. Thus, basophils play critical role in induction of and augmentation of Th2/IgE response.

Research Products

• [Journal Article] Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system (2008)
  • Author(s): Kondo Y, Yoshimoto T, Yasuda K, Futatsugi-Yumikura S, Morimoto M, Hayashi N, Hoshino T, Fujimoto J, Nakanishi K.
  • Journal Title: Int.Immunol 20 Pages: 791-800
  • NAID: 10021241671
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. (2008)
  • Author(s): Kondo Y, Yoshimoto T, Yasuda K, Futatsugi-YumikuraS, Morimoto M, Hayashi N, Hoshino T, Fujimoto J, Nakanishi K.
  • Journal Title: Int. Immunol. 20 Pages: 791-800
  • NAID: 10021241671
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Type 1 cytokine/chemokine production by mouse NK cells following activation on their TLR/MyD88-mediated pathways (2007)
  • Author(s): Sawaki, J., Tsutsui, H., Hayashi, N., Yasuda, K., Akira, S., Tanizawa, T. and Nakanishi, K.
  • Journal Title: Int.Immunol 19・3 Pages: 311-320
  • NAID: 10020111348
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Interleukin-18 regulates T helper 1 or 2 immune responses of human cord blood CD4^+ Vα24^+Vβ1^+ natural killer T cells (2007)
  • Author(s): Fujibayashi, Y., Fujimori, Y., Kasumoto, I., Kai, S., Hara, H., Okamura, H., Tsutsui, H., Ogawa, H. and Nakanishi, K.
  • Journal Title: Int.J.Mol.Med. 20 Pages: 241-245
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] T helper 1 cells stimulated with ovalbumin and IL-18 induce airway hyperresponsiveness and lung fibrosis by IFN-γ and IL-13 production (2007)
  • Author(s): Hayashi, N., Yoshimoto, T., Izuhara, K., Matsui, K., Tanaka, T. and Nakanishi, K.
  • Journal Title: Proc.Natl.Acad.Sci.USA. 104 Pages: 14765-14770
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] IL-27 suppresses Th2 cell development and Th2 cytokines production from polarized Th2 cells:a novel therapeutic way for Th2-mediated allergic inflammation (2007)
  • Author(s): Yoshimoto, T., Yoshimoto, T., Yasuda, K., Mizuguchi, J., and Nakanishi, K
  • Journal Title: J.Immunol. 179 Pages: 4415-4423
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 「研究成果報告書概要(欧文)」より (2007)
  • Author(s): Sawaki, J., Tsutsui. H., Hayashi, N., Yasuda. K., Akira, S.
  • Journal Title: Int. Immunol. Pages: 311-320
• [Journal Article] Type 1 cytokine/chemokine production by mouse NK cells following activation on their TLR/MyD88-mediated pathways. (2007)
  • Author(s): Tanizawa. T., Nakanishi. K.
  • Journal Title: Int. J. Mol. Med. 20 Pages: 241-245
  • NAID: 10020111348
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interleukin-18 regulates T helper 1 or 2 immune responses of human cord blood CD4^+Vα24^+Vβ11^+ natural killer T cells. (2007)
  • Author(s): Fujibayashi, Y., Ftriimori, Y., Kasumoto, I., Kai. S. Hara. H., Okamura, H., Tsutsui, H. Ozawa, H., Nakanishi, K.
  • Journal Title: Int. J. Mol. Med. 20 Pages: 241-245
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Type 1 cytokine/chemokine production by mouse NK cells following activation on their TLR/MyD88-mediated pathways (2007)
  • Author(s): Sawaki, J., Tsutsui, H., Hayashi, N., Yasuda, K., Akira, S., Tanizawa, T., Nakanishi, K.
  • Journal Title: Int.Immunol 19 Pages: 311-320
  • NAID: 10020111348
  • Peer Reviewed
• [Journal Article] Interleukin-18 regulates T helper 1 or 2 immune responses ofhuman cord blood CD4^+Va24^+Vβ11^+natural killer T cells (2007)
  • Author(s): Fujibayashi, Y., Fuiimori, Y., Kasumoto, I., Kai, S., Hara, H., Okamura, H., Tsutsui, H., Ogawa, H., Nakanishi, K.
  • Journal Title: Int J.Mol.Med 20 Pages: 241-245
  • Peer Reviewed
• [Journal Article] Role of innate immune response in liver regeneration (2007)
  • Author(s): Iimuro, Y., Seki, E., Son, G., Tsutsui, H., Nakanishi, K., Fujimoto, J
  • Journal Title: J.Gastroenterol.Hepatol 22 Pages: 57-58
  • Peer Reviewed
• [Journal Article] Thelper 1 cells stimulated with ovalbumin and IL-18 induceairway hyperresponsiveness and lung fibrosis by IFN-y and IL-13production (2007)
  • Author(s): Hayashi, N., Yoshimoto, T., Izuhara, K., Matsui, K., Tanaka, T., Nakanishi, K
  • Journal Title: Proc.Natl.Acad.Sci.USA 104 Pages: 14765-14770
  • Peer Reviewed
• [Journal Article] IL-27 suppresses Th2 cell development and Th2 cytokines production from polarized Th2 cells a novel therapeutic way forTh2-mediated allergic inflammation (2007)
  • Author(s): Yoshimoto, T., Yoshimoto, T., Yasuda, K., Mizuguchi, J., Nakanishi, K
  • Journal Title: J.Immunol 179 Pages: 4415-4423
  • Peer Reviewed
• [Journal Article] Progress in the molecular biology of malaria and the immunology of nematode infections. (2007)
  • Author(s): Arizono, N., Nakanishi, K., Horii, T., Tanabe, K.
  • Journal Title: Tends in Parasitology 23・4 Pages: 175-181
• [Journal Article] Type 1 cytokine/chemokine production by mouse NK cells following activation on their TLR/MyD88-mediated pathways. (2007)
  • Author(s): Sawaki, J., Tsutsui, H., Hayashi, N., Yasuda, K., Akira, S., Tanizawa, T., Nakanishi, K.
  • Journal Title: Int.Immunol. 19・3 Pages: 311-320
  • NAID: 10020111348
• [Journal Article] Human mast cell chymase cleaves pro-IL-18 and generates a novel and biologically active IL-18 fragment. (2006)
  • Author(s): Omoto, Y., Tokime, K., Yamanaka, K., Habe, K., Morioka, T., Kurokawa, I., Tsutsui, H., Yamanishi, K., Nakanishi, K., Mizutani, H.
  • Journal Title: J.Immunol. 177・12 Pages: 8315-8319
• [Journal Article] Contribution of IL-18-induced innate T cell activation to airway inflammation with mucus hypersecretion and airway hyperresponsiveness. (2006)
  • Author(s): Ishikawa, Y., Yoshimoto, T., Nakanishi, K.
  • Journal Title: Int.Immunol. 18・6 Pages: 847-855
  • NAID: 10020618556
• [Journal Article] Contribution of interleukin-18 to atopic dermatitis-like skin inflammation induced by Staphylococcus aureus product in mice. (2006)
  • Author(s): Terada, M., Tsutsui, H., Imai, Y., Yasuda, K., Mizutani, H., Yamanishi, K., Kubo, M., Matsui, K., Sano, H., Nakanishi, K.
  • Journal Title: Proc.Natl.Acad.Sci.USA. 103・23 Pages: 8816-8821
• [Journal Article] Plasma interleukin (IL)-18 (interferon-gamma-inducing factor) and other inflammatory cytokines in patients with gouty arthritis and monosodium urate monohydrate crystal-induced secretion of IL-18. (2006)
  • Author(s): Inokuchi, T., Moriwaki, Y., Tsutsui, H., Yamamoto, A., Takahashi, S., Tsutsumi, Z., Ka, T., Nakanishi, K., Yamamoto, T.
  • Journal Title: Cytokine. 33・1 Pages: 21-27
• [Journal Article] Contribution of interleukin-18 to atopic dermatitis-like skin inflammation induced by Staphylococcus aureus product in mice. (2006)
  • Author(s): Terada, M
  • Journal Title: Proc.Natl.Acad.Sci.USA. (in press)
• [Journal Article] Contribution of Toll-like receptor/myeloid diffferentiation factor 88 signallings to murine liver regeneration. (2005)
  • Author(s): Seki, E
  • Journal Title: Hepatology 41・3 Pages: 443-450
• [Journal Article] A novel caspase-1/toll-like receptor 4-independent pathway of cell death induced by cytosolic Shigella in infected macrophages (2005)
  • Author(s): Suzuki, T
  • Journal Title: J Biol Chem. 280・14 Pages: 14042-14050
• [Journal Article] Endogenous interleukin-6 but not tumor necrosis factor-alpha, contributes to the development of toll-like receptor 4/myeloid differentiation factor 88-mediated acute arthritis in mice. (2005)
  • Author(s): Kyo, F
  • Journal Title: Arthritis Rheum 52・8 Pages: 2530-2540
• [Journal Article] IL-18 with IL-2 protects against Strongyloides venezuelensis infection by activating mucosal mast cell-dependent type 2 innate immunity. (2005)
  • Author(s): Sasaki, Y
  • Journal Title: J.Exp.Med. 202・5 Pages: 607-616
• [Journal Article] Human anti-human IL-18 antibody recognizing the IL-18-binding site 3 with IL-18 Signaling blocking activity. (2005)
  • Author(s): Hamasaki, T
  • Journal Title: J.Biochem. 138・4 Pages: 433-442
• [Journal Article] T helper 1 cells stimulated with ovalbumin and IL-18 induce airway hyperresponsiveness and lung fibrosis by IFN-γ and IL-13 production.
  • Author(s): Hayashi, N., Yoshimoto, T., Izuhara, K., Matsui. K. Tanaka, T., Nakanishi. K.
  • Journal Title: Proc. Natl. Acad. Sci. USA 104 Pages: 14765-14770
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] IL-27 suppresses Th2 cell development and Th2 cytokines production from polarized Th2 cells : a novel therapeutic way for Th2-mediated allergic inflammation.
  • Author(s): Yoshimoto, T., Yoshimoto, T., Yasuda. K. Mizuguchi, J., Nakanishi. K
  • Journal Title: J. Immunol. 179 Pages: 4415-4423
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Regulation of host defense against helminthes and protozoa by IL-18 and IL-27. (2007)
  • Author(s): Nakanishi, K.
  • Organizer: The 7th Awaji International forum on infection and immunity.
  • Place of Presentation: Hyogo
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] The role of IL-18 in intrinsic allergic diseases. (2006)
  • Author(s): Nakanishi, K.
  • Organizer: RCAI-JSI International symposium of Immunology.
  • Place of Presentation: Yokohama
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Interleukin 18 induces airway inflammation and hyperresponsiveness in animal models. (2005)
  • Author(s): Nakanishi, K.
  • Organizer: VI National conference of Indian academy of allergy.
  • Place of Presentation: India
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] The role of IL-18 new regulatory cytokine in allergic diseases. (2005)
  • Author(s): Nakanishi, K.
  • Organizer: International cytokine society conference.
  • Place of Presentation: Korea
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Interleukin-18 is a novel therapeutic target for intrinsic a topic dermatitis induced by staphylococcal product in mice. (2005)
  • Author(s): Tsutsui, H. Terada, M., Sano, H., Nakanishi, K.
  • Organizer: International cytokine society conference.
  • Place of Presentation: Korea
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] IL-18とアトピーモデル (2005)
  • Author(s): 善本知広
  • Total Pages: 380
  • Publisher: Molecular Medicine
• [Patent(Industrial Property Rights)] 気管支喘息発症モデル動物およびその作製方法、並びにその利用 (2006)
  • Inventor(s): 中西憲司, 善本知広
  • Industrial Property Rights Holder: 科学技術振興機構
  • Industrial Property Number: 2006-124354
  • Filing Date: 2006-04-27
• [Patent(Industrial Property Rights)] 選択的Th2免疫反応抑制 (2005)
  • Inventor(s): 中西 憲司, 他二名
  • Industrial Property Rights Holder: 中西憲司, 他二名
  • Industrial Property Number: 2005-118334
  • Filing Date: 2005-04-15
  • Description: 「研究成果報告書概要(和文)」より