Susumu Nakae

Publications (78)535.88 Total impact

• Article: IL-33-Mediated Innate Response and Adaptive Immune Cells Contribute to Maximum Responses of Protease Allergen-Induced Allergic Airway Inflammation.

  Seiji Kamijo, Haruna Takeda, Tomoko Tokura, Mayu Suzuki, Kyoko Inui, Mutsuko Hara, Hironori Matsuda, Akira Matsuda, Keisuke Oboki, Tatsukuni Ohno, Hirohisa Saito, Susumu Nakae, Katsuko Sudo, Hajime Suto, Saori Ichikawa, Hideoki Ogawa, Ko Okumura, Toshiro Takai
  [show abstract] [hide abstract]
  ABSTRACT: How the innate and adaptive immune systems cooperate in the natural history of allergic diseases has been largely unknown. Plant-derived allergen, papain, and mite allergens, Der f 1 and Der p 1, belong to the same family of cysteine proteases. We examined the role of protease allergens in the induction of Ab production and airway inflammation after repeated intranasal administration without adjuvants and that in basophil/mast cell stimulation in vitro. Papain induced papain-specific IgE/IgG1 and lung eosinophilia. Der f 1 induced Der f 1-specific IgG1 and eosinophilia. Although papain-, Der f 1-, and Der p 1-stimulated basophils expressed allergy-inducing cytokines, including IL-4 in vitro, basophil-depleting Ab and mast cell deficiency did not suppress the papain-induced in vivo responses. Protease inhibitor-treated allergens and a catalytic site mutant did not induce the responses. These results indicate that protease activity is essential to Ab production and eosinophilia in vivo and basophil activation in vitro. IL-33-deficient mice lacked eosinophilia and had reduced papain-specific IgE/IgG1. Coadministration of OVA with papain induced OVA-specific IgE/IgG1, which was reduced in IL-33-deficient mice. We demonstrated IL-33 release, subsequent IL-33-dependent IL-5/IL-13 release, and activation of T1/ST2-expressing lineage(-)CD25(+)CD44(+) innate lymphoid cells in the lung after papain inhalation, suggesting the contribution of the IL-33-type 2 innate lymphoid cell-IL-5/IL-13 axis to the papain-induced airway eosinophilia. Rag2-deficient mice, which lack adaptive immune cells, showed significant, but less severe, eosinophilia. Collectively, these results suggest cooperation of adaptive immune cells and IL-33-responsive innate cells in protease-dependent allergic airway inflammation.
  The Journal of Immunology 04/2013; · 5.79 Impact Factor
• Article: Role of interleukin-33 in innate-type immune cells in allergy.

  Susumu Nakae, Hideaki Morita, Tatsukuni Ohno, Ken Arae, Kenji Matsumoto, Hirohisa Saito
  [show abstract] [hide abstract]
  ABSTRACT: Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is preferentially and constitutively expressed in epithelial cells, and it is especially localized in the cells' nucleus. The nuclear IL-33 is released by necrotic cells after tissue injury and/or trauma, and subsequently provokes local inflammation as an alarmin, like high-mobility group box protein-1 (HMGB-1) and IL-1α. IL-33 mainly activates Th2 cells and such innate-type immune cells as mast cells, basophils, eosinophils and natural helper cells that express IL-33R (a heterodimer of IL-1 receptor-like 1 [IL-1RL1; also called ST2, T1, Der4, fit-1] and IL-1 receptor accessory protein [IL-1RAcP]). That activation causes the cells to produce Th2 cytokines, which contribute to host defense against nematodes. On the other hand, excessive and/or inappropriate production of IL-33 is also considered to be involved in the development of such disorders as allergy. In this review, we summarize current knowledge regarding the pathogenic roles of IL-33 in the development of allergic inflammation by focusing on its effects on innate-type immune cells.
  Allergology International 03/2013; 62(1):13-20.
• Article: Epithelial Cell-Derived IL-25, but Not Th17 Cell-Derived IL-17 or IL-17F, Is Crucial for Murine Asthma.

  Maho Suzukawa, Hideaki Morita, Aya Nambu, Ken Arae, Eri Shimura, Akiko Shibui, Sachiko Yamaguchi, Keigo Suzukawa, Wakako Nakanishi, Keisuke Oboki, [......], Takayuki Yoshimoto, Yoichiro Iwakura, Tatsuya Yamasoba, Ken Ohta, Katsuko Sudo, Hirohisa Saito, Ko Okumura, David H Broide, Kenji Matsumoto, Susumu Nakae
  [show abstract] [hide abstract]
  ABSTRACT: IL-17A, IL-17F, and IL-25 are ligands for IL-17RA. In the current study, we demonstrated that IL-25-deficient mice-but not IL-17A-, IL-17F-, IL-17A/F-, IL-23p19-, or retinoic acid-related orphan receptor (ROR)-γt-deficient mice-showed significant suppression of 1) the number of eosinophils and the levels of proinflammatory mediators in bronchoalveolar lavage fluids, 2) airway hyperresponsiveness to methacholine, and 3) OVA-specific IgG1 and IgE levels in the serum during OVA-induced Th2-type/eosinophilic airway inflammation. The IL-25 deficiency did not affect lung dendritic cell migration or Ag-specific memory-Th2 cell expansion during Ag sensitization. Adoptive transfer of T cells, mast cells, or bone marrow cells from IL-25-deficient mice revealed that induction of Th2-type/eosinophilic airway inflammation was dependent on activation of lung epithelial cells and eosinophils by IL-25 produced by airway structural cells such as epithelial cells but not by such hematopoietic stem-cell-origin immune cells as T cells and mast cells. Therefore, airway structural cell-derived IL-25-rather than Th17 cell-derived IL-17A and IL-17F-is responsible for induction of local inflammation by promoting activation of lung epithelial cells and eosinophils in the elicitation phase of Th2-type/eosinophilic airway inflammation. It is not required for Ag-specific Th2 cell differentiation in the sensitization phase.
  The Journal of Immunology 08/2012; 189(7):3641-52. · 5.79 Impact Factor
• Article: Interleukin-33 in allergy.

  Tatsukuni Ohno, Hideaki Morita, Ken Arae, Kenji Matsumoto, Susumu Nakae
  [show abstract] [hide abstract]
  ABSTRACT: Interleukin-33 (IL-33) is a member of the IL-1 cytokine family, which includes IL-1 and IL-18, and is considered to be important for host defense against nematodes by inducing Th2 cytokine production via the IL-33 receptor. IL-33 receptor is a heterodimer of IL-1 receptor-like 1 (IL-1RL1; also called ST2, T1, Der4, and fit-1) and IL-1 receptor accessory protein (IL-1RAcP). On the other hand, excessive and/or inappropriate production of IL-33 is considered to be involved in the development of various disorders, such as allergic and autoimmune diseases. Unlike IL-1β and IL-18, IL-33 does not seem to be secreted through the activation of inflammasomes in events such as apoptosis. However, IL-33 is localized in the nucleus of cells and is released during tissue injury associated with necrosis. This suggests that it acts as an alarmin, like IL-1α and high-mobility group box chromosomal protein-1 (HMGB-1). This review summarizes current knowledge regarding the roles of IL-33 in the functions of various cell types and the pathogenesis of allergy.
  Allergy 08/2012; 67(10):1203-14. · 6.27 Impact Factor
• Article: Potential role of γδ T cell-derived IL-17 in acute cardiac allograft rejection.

  Naoyuki Kimura, Susumu Nakae, Satoshi Itoh, Denis R Merk, Xi Wang, Yongquan Gong, Homare Okamura, Paul A Chang, Hideo Adachi, Robert C Robbins, Michael P Fischbein
  [show abstract] [hide abstract]
  ABSTRACT: Although αβ T cells are known to participate in the development of acute cardiac allograft rejection, the role of γδ T cells remains poorly understood. We hypothesized that γδ T cells contribute to acute allograft rejection thru interleukin (IL)-17 production. Donor hearts from FVB mice (H-2q) were heterotopically transplanted into C57BL/6-wild type (WT) and γδ T cell-deficient (TCRδ-/-) recipient mice (H-2b). Overall graft survival was monitored. Graft infiltrating cell profile, including γδ T cell subtype, cytokine expression, and myeloperoxidase activity were measured by flow cytometry, TaqMan (Applied Biosystems, Carlsbad, CA) polymerase chain reaction, and myeloperoxidase assay, respectively, on postoperative days 3 and 6. Graft survival was prolonged in TCRδ-/- recipients compared with WT controls. Graft infiltrating cells, including CD45+, CD4+, CD8+, and Gr1+ cells were significantly decreased in TCRδ-/- recipients compared with WT. Donor hearts transplanted into TCRδ-/- recipients had reduced IL-17 and IL-6 messenger RNA expression. Corroborating the gene expression, intracellular cytokine staining showed decreased IL-17 producing cells in TCRδ-/- recipients. Finally, Vγ1+ and Vγ4+ T cells did not produce IL-17, although both represent 20% to 30% total graft infiltrating γδ T cells. The γδ T cells promote acute cardiac allograft rejection, presumably by producing IL-17. The γδ T cell depletion may prove beneficial in prolonging allograft survival by suppressing IL-17 production.
  The Annals of thoracic surgery 05/2012; 94(2):542-8. · 3.74 Impact Factor
• Article: Th17 cell-derived IL-17 is dispensable for B cell antibody production.

  Akiko Shibui, Eri Shimura, Aya Nambu, Sachiko Yamaguchi, Warren J Leonard, Ko Okumura, Sumio Sugano, Katsuko Sudo, Susumu Nakae
  [show abstract] [hide abstract]
  ABSTRACT: IL-17, which is preferentially produced by Th17 cells, is important for host defense against pathogens and is also involved in the development of autoimmune and allergic disorders. Antibody (Ab) production was shown to be impaired in IL-17-deficient mice, suggesting that IL-17 may promote B cell activation and direct secretion of Ab. However, the precise role of IL-17 in Ab production by B cells remains unclear. In the present study, we found constitutive expression of IL-17R in murine splenic B cells. Nevertheless, IL-17, IL-17F or IL-25 alone could not induce Ab production by B cells even in the presence of agonistic anti-CD40 Ab. IL-17 also could not affect IFN-γ-, IL-4- or TGF-β1-mediated Ig class-switching. Furthermore, in co-cultures of B cells and IL-17(-/-) CD4(+) T cells or IL-17(-/-) Th17 cells, IL-17 deficiency did not influence Ab production by B cells in vitro, suggesting that Th17 cell-derived IL-17 was not required for B cell Ab production through T cell-B cell interaction in vitro. Thus, in vivo, IL-17 may be indirectly involved in Ab production by enhancing production of B cell activator(s) by other immune cells.
  Cytokine 04/2012; 59(1):108-14. · 3.02 Impact Factor
• Article: ST2 requires Th2-, but not Th17-, type airway inflammation in epicutaneously antigen- sensitized mice.

  Hideaki Morita, Ken Arae, Tatsukuni Ohno, Naoki Kajiwara, Keisuke Oboki, Akio Matsuda, Hajime Suto, Ko Okumura, Katsuko Sudo, Takao Takahashi, Kenji Matsumoto, Susumu Nakae
  [show abstract] [hide abstract]
  ABSTRACT: IL-33 is known to induce Th2-type cytokine production by various types of cells through its receptors, ST2 and IL-1RAcP. Polymorphism in the ST2 and/or IL-33 genes was found in patients with atopic dermatitis and asthma, implying that the IL-33/ST2 pathway is closely associated with susceptibility to these diseases. Exposure to allergens through damaged skin is suspected to be a trigger for allergen sensitization, resulting in development of such allergic disorders as asthma and atopic dermatitis. To elucidate the role(s) of the IL-33/ST2 pathway in asthma in individuals who had been epicutaneously sensitized to an antigen, wild-type and ST2-/- mice were epicutaneously sensitized with ovalbumin (OVA) and then were intranasally challenged with OVA. The degree of airway inflammation, the number of leukocytes and the activities of myeloperoxidase (MPO) and eosinophil peroxidase (EPO) in bronchoalveolar lavage fluids (BALFs), The levels of cytokines and chemokines in lungs and OVA-specific IgE levels in sera were determined by histological analysis, a hemocytometer, colorimetric assay, quantitative PCR or ELISA, respectively. The number of eosinophils in BALFs, the levels of Th2 cytokines and chemoattractants in the lungs and OVA-specific IgE in sera from ST2-/- mice were significantly reduced compared with wild-type mice. Although the number of neutrophils in BALFs and the pulmonary levels of IL-17 were comparable in both mice, the levels of MPO activity in BALFs and neutrophil chemoattractants in the lung were reduced in ST2-/- mice. The IL-33/ST2 pathway is crucial for Th2-cytokine-mediated eosinophilic, rather than Th17-cytokine-mediated neutrophilic, airway inflammation in mice that had been epicutaneously sensitized with antigens and then challenged with antigen.
  Allergology International 02/2012; 61(2):265-73.
• Article: Interleukin-16 deficiency suppresses the development of chronic rejection in murine cardiac transplantation model.

  Naoyuki Kimura, Satoshi Itoh, Susumu Nakae, Robert C Axtell, Jeffrey B Velotta, Ernst Jan Bos, Denis R Merk, Yongquan Gong, Homare Okamura, Claude M Nagamine, Hideo Adachi, Hardy Kornfeld, Robert C Robbins, Michael P Fischbein
  [show abstract] [hide abstract]
  ABSTRACT: IL-16 promotes the recruitment of various cells expressing CD4, a receptor for IL-16. The precise role of IL-16 in transplant rejection remains unknown; therefore, the present study investigated the contribution of IL-16 to the development of chronic rejection in heart transplants. C-H-2(bm12)KhEg (H-2(bm12)) donor hearts were transplanted into (1) IL-16-deficient (IL-16(-/-)) C57BL/6J or (b) wild type (WT) control recipients (MHC class II mismatch). Grafts were harvested at 52 days, parenchymal rejection was assessed by the ISHLT grading system, and CAV was examined morphometrically. Graft infiltrating cells were detected 10 and 52 days after transplantation. Intragraft cytokine and chemokine profiles were assessed. To confirm the role of IL-16 in CAV development, C-H-2(bm12)KhEg (H-2(bm12)) donor hearts were transplanted into C57BL/6J WT recipients treated with (1) anti-IL-16-neutralization monoclonal antibody or (b) control immunoglobulin G. Grafts were harvested at 52 days, and CAV was quantified morphometrically. Graft-infiltrating cells were examined histologically. Parenchymal rejection and CAV was significantly attenuated in donor hearts transplanted into IL-16(-/-) recipient mice compared with WT controls. Donor hearts transplanted into IL-16(-/-) recipients had a significant reduction in coronary artery luminal occlusion, intima-to-media ratio, and percentage of diseased vessels. CAV was associated with decreased donor organ inflammation, as well as donor organ cytokine (IL-1β and IL-6) and chemokine (MCP-1 and KC) protein expression. Intimal proliferation and inflammatory cell infiltration were significantly reduced in hearts transplanted into recipients treated with an IL-16-neutralization antibody. IL-16-deficiency reduced graft inflammatory cell recruitment, and allograft inflammatory cytokine and chemokine production. Therefore, IL-16 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.
  The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 12/2011; 30(12):1409-17. · 3.54 Impact Factor
• Article: Interleukin-17 accelerates allograft rejection by suppressing regulatory T cell expansion.

  Satoshi Itoh, Naoyuki Kimura, Robert C Axtell, Jeffrey B Velotta, Yongquan Gong, Xi Wang, Naoki Kajiwara, Aya Nambu, Eri Shimura, Hideo Adachi, Yoichiro Iwakura, Hirohisa Saito, Ko Okumura, Katsuko Sudo, Lawrence Steinman, Robert C Robbins, Susumu Nakae, Michael P Fischbein
  [show abstract] [hide abstract]
  ABSTRACT: Interleukin-17 (IL-17), which is predominantly produced by T helper 17 cells distinct from T helper 1 or T helper 2 cells, participates in the pathogenesis of infectious, autoimmune, and allergic disorders. However, the precise role in allograft rejection remains uncertain. In the present study, we investigated the role of IL-17 in acute allograft rejection using IL-17-deficient mice. Donor hearts from FVB mice were heterotopically transplanted into either C57BL/6J-IL-17-deficient (IL-17(-/-)) or -wild-type mice. Allograft survival was significantly prolonged in IL-17(-/-) recipient mice due to reduced local inflammation accompanied by decreased inflammatory cell recruitment and cytokine/chemokine expression. IL-17(-/-) recipient mice exhibited decreased IL-6 production and reciprocally enhanced regulatory T cell expansion, suggesting a contribution of regulatory T cells to prolonged allograft survival. Indeed, allografts transplanted into anti-CD25 mAb-treated IL-17(-/-) recipient mice (regulatory T cell-depleted) developed acute rejection similar to wild-type recipient mice. Surprisingly, we found that gamma delta T cells rather than CD4(+) and CD8(+) T cells were key IL-17 producers in the allografts. In support, equivalent allograft rejection was observed in Rag-2(-/-) recipient mice engrafted with either wild-type or IL-17(-/-) CD4(+) and CD8(+) T cells. Finally, hearts transplanted into gamma delta T cell-deficient mice resulted in decreased allograft rejection compared with wild-type controls. During heart transplantation, (1) IL-17 is crucial for acceleration of acute rejection; (2) IL-17-deficiency enhances regulatory T cell expansion; and (3) gamma delta T cells rather than CD4(+) and CD8(+) T cells are a potential source of IL-17. IL-17 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.
  Circulation 09/2011; 124(11 Suppl):S187-96. · 14.74 Impact Factor
• Article: Interleukin-17A is involved in enhancement of tumor progression in murine intestine.

  Kiyotetsu Oshiro, Hideyasu Kohama, Masayuki Umemura, Catherine Uyttenhove, Kyoko Inagaki-Ohara, Takeshi Arakawa, Mamoru Harada, Susumu Nakae, Yoichiro Iwakura, Tadashi Nishimaki, Goro Matsuzaki
  [show abstract] [hide abstract]
  ABSTRACT: Interleukin (IL)-17A is a cytokine involved in neutrophilic inflammation but the role of IL-17A in anti-tumor immunity is controversial because both pro- and anti-tumor activities of IL-17A have been reported. We hypothesized that constitutive expression of IL-17A in intestinal environment modifies tumor growth. To address the issue, mice were inoculated into subserosa of cecum (i.c.) with murine EL4 lymphoma expressing a model tumor antigen, and tumor growth was monitored. IL-17A-producing cells were detected both in tumor mass and in normal intestinal tissue of i.c. tumor-bearing wild type mice. Tumor size in the wild-type mice was significantly higher than that in the cecum of IL-17A gene-knockout mice. Furthermore, anti-IL-17A monoclonal antibody treatment of wild-type mice resulted in decreased tumor size in the cecum. Model tumor-antigen-specific interferon-γ production was not modified in draining mesenteric lymph node cells in the absence or after neutralization of IL-17A. All the results suggest that constitutive expression of IL-17A in intestine enhances tumor growth, and anti-IL-17A antibody treatment is a candidate of a new anti-tumor immunotherapy against intestinal tumors.
  Immunobiology 09/2011; 217(1):54-60. · 3.20 Impact Factor
• Article: N-acetylglucosaminyltransferase V-deficiency increases susceptibility to murine malaria.

  Akiko Shibui, Junko Doi, Mohammed E M Tolba, Chiharu Shiraishi, Yoshitaka Sato, Shumpei Ishikawa, Junichi Watanabe, Sadao Nogami, Susumu Nakae, Sumio Sugano, Nobumichi Hozumi
  [show abstract] [hide abstract]
  ABSTRACT: It is considered that several glycoproteins on erythrocytes in mammalian species are involved in malaria parasite infection. To elucidate the role of N-glycans on malaria parasite infection, we induced experimental murine malaria infection (using Plasmodium berghei ANKA) in mice deficient in N-acetylglucosaminyltransferase V (Mgat5), which is one of the enzymes involved in β1,6-GlcNAc N-glycan biosynthesis. After infection, Mgat5(-/-) mice showed severe body weight loss and parasitemia compared with wild-type mice. The Mgat5(-/-) mice, but not wild-type mice, also showed severe pathology accompanied by marked infiltration of plasma cells into the lungs and liver. These results suggest that β1,6-GlcNAc N-glycans on/in host erythrocytes may interfere with invasion of the parasites and progression to severe malaria.
  Experimental Parasitology 07/2011; 129(3):318-21. · 2.12 Impact Factor
• Article: Alteration of immune responses by N-acetylglucosaminyltransferase V during allergic airway inflammation.

  Akiko Shibui, Aya Nambu, Eri Shimura, Sachiko Yamaguchi, Chiharu Shiraishi, Yoshitaka Sato, Ko Okumura, Sumio Sugano, Nobumichi Hozumi, Susumu Nakae
  [show abstract] [hide abstract]
  ABSTRACT: β-1,6-N-acetylglucosaminyltransferase V (Mgat5 or GlcNac-TV), which is involved in the glycosylation of proteins, is known to be important for down-regulation of TCR-mediated T-cell activation and negatively regulates induction of contact dermatitis and experimental autoimmune encephalomyelitis. However, the role of Mgat5 in the induction of allergic airway inflammation remains unclear. To elucidate the role of Mgat5 in the pathogenesis of allergic airway inflammation, ovalbumin (OVA)-induced airway inflammation was induced in Mgat5-deficient mice. The OVA-specific lymphocyte proliferation and cytokine production levels, OVA-specific IgG1, IgG2a and IgE levels in the serum, and the number of leukocytes and cytokine levels in the bronchoalveolar lavage (BAL) fluid were compared between wild-type and Mgat5-deficient mice. OVA-specific lymphocyte proliferation and production of IFN-γ and IL-10, but not IL-4, were increased in Mgat5-deficient mice, suggesting that Th2-type immune responses are seemed to be suppressed by increased IFN-γ and IL-10 production in these mice. However, Th2-type responses such as OVA-specific IgG1, but not IgE, and IL-5 levels in BAL fluids were increased in Mgat5-deficient mice. Meanwhile, the number of eosinophils was normal, but the numbers of neutrophils, macrophages and lymphocytes were reduced, in these mutant mice during OVA-induced airway inflammation. Mgat5-dependent glycosylation of proteins can modulate acquired immune responses, but it is not essential for the development of OVA-induced eosinophilic airway inflammation.
  Allergology International 04/2011; 60(3):345-54.
• Article: Cimetidine enhances antigen-specific IgE and Th2 cytokine production.

  Ken Arae, Keisuke Oboki, Tatsukuni Ohno, Masako Hirata, Susumu Nakae, Haruhiko Taguchi, Hirohisa Saito, Toshiharu Nakajima
  [show abstract] [hide abstract]
  ABSTRACT: Treatment with anti-ulcer drugs has been shown to enhance IgE production against food antigens. However, little is known about the immunological effects of cimetidine, a histamine receptor type 2 (H2R) antagonist that is widely used as an anti-ulcer drug, in allergy. Therefore, the present study investigated the role of cimetidine in Th2 immune responses in mice. BALB/c mice were immunized intraperitoneally with ovalbumin (OVA) with and without cimetidine. The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA-specific IgG(1), IgG(2a) and/or IgE in sera from these mice were determined by ELISA. Administration of cimetidine to OVA-sensitized BALB/c mice promoted Th2 cytokine secretion by OVA-stimulated spleen cells in vitro and increased serum levels of OVA-specific IgE, IgG(1) and IgG(2a). These results indicate that cimetidine can enhance Th2 responses, suggesting that cimetidine may contribute to IgE production in allergies.
  Allergology International 04/2011; 60(3):339-44.
• Source

  Available from: Keisuke Oboki

  Article: IL-33 and Airway Inflammation.

  Keisuke Oboki, Susumu Nakae, Kenji Matsumoto, Hirohisa Saito
  [show abstract] [hide abstract]
  ABSTRACT: Interleukin-33 (IL-33) is the 11th member of IL-1 cytokine family which includes IL-1 and IL-18. Unlike IL-1β and IL-18, IL-33 is suggested to function as an alarmin that is released upon endothelial or epithelial cell damage and may not enhance acquired immune responses through activation of inflammasome. ST2, a IL-33 receptor component, is preferentially expressed by T-helper type (Th) 2 cells, mast cells, eosinophils and basophils, compared to Th1 cells, Th17 cells and neutrophils. Thus, IL-33 profoundly enhances allergic inflammation through increased expression of proallergic cytokines and chemokines. Indeed, IL-33 and its receptor genes are recognized as the most susceptible genes for asthma by several recent genomewide association studies. It has also recently been shown that IL-33 plays a crucial role in innate eosinophilic airway inflammation rather than acquired immune responses such as IgE production. As such, IL-33 provides a unique therapeutic way for asthma, i.e., ameliorating innate airway inflammation.
  Allergy, asthma & immunology research 04/2011; 3(2):81-8. · 1.91 Impact Factor
• Article: Leptin enhances survival and induces migration, degranulation, and cytokine synthesis of human basophils.

  Maho Suzukawa, Hiroyuki Nagase, Ikuko Ogahara, Kaiyu Han, Hiroyuki Tashimo, Akiko Shibui, Rikiya Koketsu, Susumu Nakae, Masao Yamaguchi, Ken Ohta
  [show abstract] [hide abstract]
  ABSTRACT: Basophils are the rarest leukocytes in human blood, but they are now recognized as one of the most important immunomodulatory as well as effector cells in allergic inflammation. Leptin, a member of the IL-6 cytokine family, has metabolic effects as an adipokine, and it is also known to participate in the pathogenesis of inflammatory reactions. Because there is an epidemiologic relationship between obesity and allergy, we examined whether basophil functions are modified by leptin. We found that human basophils express leptin receptor (LepR) at both the mRNA and surface protein levels, which were upregulated by IL-33. Leptin exerted strong effects on multiple basophil functions. It induced a strong migratory response in human basophils, similar in potency to that of basophil-active chemokines. Also, leptin enhanced survival of human basophils, although its potency was less than that of IL-3. Additionally, CD63, a basophil activation marker expressed on the cell surface, was upregulated by leptin, an effect that was neutralized by blocking of LepR. Assessments of basophil degranulation and cytokine synthesis found that leptin showed a strong priming effect on human basophil degranulation in response to FcεRI aggregation and induced Th2, but not Th1, cytokine production by the cells. In summary, the present findings indicate that leptin may be a key molecule mediating the effects of adipocytes on inflammatory cells such as basophils by binding to LepR and activating the cellular functions, presumably exacerbating allergic inflammation.
  The Journal of Immunology 03/2011; 186(9):5254-60. · 5.79 Impact Factor
• Source

  Available from: u-tokyo.ac.jp

  Article: Functional specialization of interleukin-17 family members.

  Yoichiro Iwakura, Harumichi Ishigame, Shinobu Saijo, Susumu Nakae
  [show abstract] [hide abstract]
  ABSTRACT: Interleukin-17A (IL-17A) is the signature cytokine of the recently identified T helper 17 (Th17) cell subset. IL-17 has six family members (IL-17A to IL-17F). Although IL-17A and IL-17F share the highest amino acid sequence homology, they perform distinct functions; IL-17A is involved in the development of autoimmunity, inflammation, and tumors, and also plays important roles in the host defenses against bacterial and fungal infections, whereas IL-17F is mainly involved in mucosal host defense mechanisms. IL-17E (IL-25) is an amplifier of Th2 immune responses. The functions of IL-17B, IL-17C, and IL-17D remain largely elusive. In this review, we describe the identified functions of each IL-17 family member and discuss the potential of these molecules as therapeutic targets.
  Immunity 02/2011; 34(2):149-62. · 21.64 Impact Factor
• Source

  Available from: Keisuke Oboki

  Article: Paracrine IL-33 stimulation enhances lipopolysaccharide-mediated macrophage activation.

  Tatsukuni Ohno, Keisuke Oboki, Hideaki Morita, Naoki Kajiwara, Ken Arae, Shizuko Tanaka, Masako Ikeda, Motoyasu Iikura, Taishin Akiyama, Jun-ichiro Inoue, Kenji Matsumoto, Katsuko Sudo, Miyuki Azuma, Ko Okumura, Thomas Kamradt, Hirohisa Saito, Susumu Nakae
  [show abstract] [hide abstract]
  ABSTRACT: IL-33, a member of the IL-1 family of cytokines, provokes Th2-type inflammation accompanied by accumulation of eosinophils through IL-33R, which consists of ST2 and IL-1RAcP. We previously demonstrated that macrophages produce IL-33 in response to LPS. Some immune responses were shown to differ between ST2-deficient mice and soluble ST2-Fc fusion protein-treated mice. Even in anti-ST2 antibody (Ab)-treated mice, the phenotypes differed between distinct Ab clones, because the characterization of such Abs (i.e., depletion, agonistic or blocking Abs) was unclear in some cases. To elucidate the precise role of IL-33, we newly generated neutralizing monoclonal Abs for IL-33. Exogenous IL-33 potentiated LPS-mediated cytokine production by macrophages. That LPS-mediated cytokine production by macrophages was suppressed by inhibition of endogenous IL-33 by the anti-IL-33 neutralizing mAbs. Our findings suggest that LPS-mediated macrophage activation is accelerated by macrophage-derived paracrine IL-33 stimulation.
  PLoS ONE 01/2011; 6(4):e18404. · 4.09 Impact Factor
• Chapter: The Roles of IL-17A and IL-17F in Mucosal Infection and Allergy

  Harumichi Ishigame, Susumu Nakae, Yoichiro Iwakura
  [show abstract] [hide abstract]
  ABSTRACT: TH17 cells are a subset of CD4+ helper T cells that produce IL-17A, IL-17F, IL-9, IL-21, and IL-22. They play an important role in promoting allergic and auto-immune responses as well as in protecting hosts against pathogens. Because IL-17A and IL-17F have the highest homology among IL-17 family members and bind the same IL-17RA and IL-17RC receptor complex, it is suggested that these two cytokines have similar functions. However, accumulating evidence suggests that these cytokines have overlapping yet distinct roles in the immune system. In this review, we introduce how IL-17A and IL-17F are involved in inflammatory immune responses and host defense mechanisms and discuss their relationship with other cytokines in the development of inflammatory and infectious diseases.
  12/2010: pages 269-297;
• Source

  Available from: Keisuke Oboki

  Article: Development of IL-17-mediated delayed-type hypersensitivity is not affected by down-regulation of IL-25 expression.

  Akina Ishii, Keisuke Oboki, Aya Nambu, Hideaki Morita, Tatsukuni Ohno, Naoki Kajiwara, Ken Arae, Hajime Sudo, Ko Okumura, Hirohisa Saito, Susumu Nakae
  [show abstract] [hide abstract]
  ABSTRACT: IL-25, which is a member of the IL-17 family, induces Th2 cell differentiation and Th2 cytokine production, contributing to induction of Th2-type immune responses and diseases, as a result of which it suppresses Th1- and Th17-type immune responses. To elucidate the role of IL-25 in the pathogenesis of IL-17-mediated delayed-type hypersensitivity (DTH), IL-25-deficient mice were sensitized with methylated BSA (mBSA), and then a DTH reaction was induced by mBSA challenge. mBSA-specific T-cell induction was assessed on the basis of cell proliferation and cytokine production. The DTH reaction was evaluated on the basis of tissue swelling, histology and inflammatory mediator expression. IL-25 expression was markedly reduced in local DTH lesions. However, mBSA-specific Th1, Th2 and Th17 cell induction, and the mBSA-induced DTH reaction were comparable in IL-25-deficient and wild-type mice. IL-25 is not essential for differentiation of Th1, Th2 and Th17 cells in the sensitization phase or induction of local inflammation in the elicitation phase of the mBSA-induced DTH reaction.
  Allergology International 12/2010; 59(4):399-408.
• Article: Phosphodiesterase 4B is essential for T(H)2-cell function and development of airway hyperresponsiveness in allergic asthma.

  S-L Catherine Jin, Sho Goya, Susumu Nakae, Dan Wang, Matthew Bruss, Chiaoyin Hou, Dale Umetsu, Marco Conti
  [show abstract] [hide abstract]
  ABSTRACT: Cyclic AMP (cAMP) signaling modulates functions of inflammatory cells involved in the pathogenesis of asthma, and type 4 cAMP-specific phosphodiesterases (PDE4s) are essential components of this pathway. Induction of the PDE4 isoform PDE4B is necessary for Toll-like receptor signaling in monocytes and macrophages and is associated with T cell receptor/CD3 in T cells; however, its exact physiological function in the development of allergic asthma remains undefined. We investigated the role of PDE4B in the development of allergen-induced airway hyperresponsiveness (AHR) and T(H)2-driven inflammatory responses. Wild-type and PDE4B(-/-) mice were sensitized and challenged with ovalbumin and AHR measured in response to inhaled methacholine. Airway inflammation was characterized by analyzing leukocyte infiltration and cytokine accumulation in the airways. Ovalbumin-stimulated cell proliferation and T(H)2 cytokine production were determined in cultured bronchial lymph node cells. Mice deficient in PDE4B do not develop AHR. This protective effect was associated with a significant decrease in eosinophils recruitment to the lungs and decreased T(H)2 cytokine levels in the bronchoalveolar lavage fluid. Defects in T-cell replication, T(H)2 cytokine production, and dendritic cell migration were evident in cells from the airway-draining lymph nodes. Conversely, accumulation of the T(H)1 cytokine IFN-γ was not affected in PDE4B(-/-) mice. Ablation of the orthologous PDE4 gene PDE4A has no impact on airway inflammation. By relieving a cAMP-negative constraint, PDE4B plays an essential role in T(H)2-cell activation and dendritic cell recruitment during airway inflammation. These findings provide proof of concept that PDE4 inhibitors with PDE4B selectivity may have efficacy in asthma treatment.
  The Journal of allergy and clinical immunology 11/2010; 126(6):1252-9.e12. · 9.17 Impact Factor