T Kishimoto

Osaka University, Suika, Ōsaka, Japan

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Publications (1000)5411.65 Total impact

  • D Hiraoka, E Okumura, T Kishimoto
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    ABSTRACT: Akt, also known as protein kinase B, has a central role in various signaling pathways that regulate cellular processes such as metabolism, proliferation and survival. On stimulation, phosphorylation of the activation loop (A-loop) and hydrophobic motif (HM) of Akt by the kinase phosphoinositide-dependent kinase 1 (PDK1) and the mammalian target of rapamycin complex 2 (mTORC2), respectively, results in Akt activation. A well-conserved threonine in the turn motif (TM) is also constitutively phosphorylated by mTORC2 and contributes to the stability of Akt. The role of TM phosphorylation in HM and A-loop phosphorylation has not been sufficiently evaluated. Using starfish oocytes as a model system, this study provides the first evidence that TM phosphorylation has a negative role in A-loop phosphorylation. In this system, the maturation-inducing hormone, 1-methyladenine, stimulates Akt to reinitiate meiosis through activation of cyclin B-Cdc2. The phosphorylation status of Akt was monitored via introduction of exogenous human Akt (hAkt) in starfish oocytes. TM and HM phosphorylation was inhibited by microinjection of an anti-starfish TOR antibody, but not by rapamycin treatment, suggesting that both phosphorylation events depend on TORC2, as reported in mammalian cells. A single or double alanine substitution at each of three phosphorylation residues revealed that TM phosphorylation renders Akt susceptible to dephosphorylation on the A-loop. When A-loop phosphatase was inhibited by okadaic acid (OA), TM phosphorylation still reduced A-loop phosphorylation, suggesting that the effect is caused at least partially through reduction of sensitivity to PDK1. Negative regulation by TM phosphorylation was also observed in constitutively active Akt and was functionally reflected in meiosis resumption. By contrast, HM phosphorylation enhanced A-loop phosphorylation and achieved full activation of Akt via a mechanism at least partially independent of TM phosphorylation. These observations provide new insight into the mechanism controlling Akt phosphorylation in the cell.
    Oncogene 05/2011; 30(44):4487-97. DOI:10.1038/onc.2011.155 · 8.56 Impact Factor
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    Toshio Tanaka, Masashi Narazaki, Tadamitsu Kishimoto
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    ABSTRACT: Interleukin (IL)-6 is a cytokine with multiple biological activities. It contributes to host defense against pathogens, whereas accelerated production of IL-6 plays a significant pathological role in various diseases. Clinical trials have demonstrated the efficacy of tocilizumab, a humanized anti-IL-6 receptor antibody, for patients with rheumatoid arthritis, Castleman's disease or juvenile idiopathic arthritis, leading to approval of this innovative drug for the treatment of these diseases. Since IL-6 has been demonstrated to play a significant role in the development of various other autoimmune and inflammatory diseases, tocilizumab can be expected to become a novel drug for such diseases as well.
    FEBS letters 03/2011; 585(23):3699-709. DOI:10.1016/j.febslet.2011.03.023 · 3.34 Impact Factor
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    ABSTRACT: Objective. Our aim was to investigate the effects of IL-6 blockade on the progression of Mycobacterium tuberculosis (TB) and compare them with those of TNF-α blockade in mice. Methods. Mice were intravenously infected with TB and injected with antibodies. Survival was monitored and histological and immunological studies were carried out. Results. All anti-IL-6R Ab-treated mice and 8 of 10 control mice survived until sacrificed 224 days after TB challenge, whereas anti-TNF-α Ab-treated mice all died between 120 and 181 days. Anti-IL-6R Ab-treated mice exhibited no significant differences in TB CFU in organs, including the lungs, and no deterioration in histopathology compared to control mice at 4 weeks. In contrast, anti-TNF-α Ab-treated mice exhibited increased TB CFU and greater progression of histopathological findings in organs than control mice. Spleen cells from anti-TNF-α Ab-treated mice had decreased antigen-specific response in IFN-γ release and proliferation assays. The results in anti-IL-6R Ab-treated mice suggest that spleen cell responses were decreased to a lesser degree. Similar results were obtained in IL-6 knockout (KO) mice, compared with TNF receptor 1 (TNFR1) KO and TNFR1/IL-6 double KO (DKO) mice. Conclusion. IL-6R blockade promotes the progression of TB infection in mice far less than TNF-α blockade.
    Clinical and Developmental Immunology 02/2011; 2011:404929. DOI:10.1155/2011/404929 · 2.93 Impact Factor
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    ABSTRACT: Ankylosing spondylitis (AS) is a chronic inflammatory osteoarticular disease. Although the etiology remains unknown, proinflammatory cytokines, such as tumor necrosis factor α and interleukin-6, have been implicated in the development of AS. Here, we report that a patient with AS, whose disease had been refractory to conventional treatment regimens and who needed to receive continuous corticosteroid, responded well to tocilizumab. While further clinical evaluation is required, tocilizumab may be an optional treatment for AS.
    Modern Rheumatology 02/2011; 21(4):436-9. DOI:10.1007/s10165-011-0416-9 · 2.21 Impact Factor
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    ABSTRACT: PURPOSE. Both Th17 and Th1 cells contribute to experimental autoimmune uveoretinitis (EAU). Interleukin-6 (IL-6) blockade inhibits Th17 differentiation in EAU and potently suppresses ocular inflammation, although its effect on Th1 cells is unknown. To clarify the mechanism of IL-6 blockade, the authors investigated T helper cells with particular focus on Th1 and regulatory T cells (Treg) in EAU of IL-6 gene knockout (KO) mice. METHODS. EAU was induced in wild-type (WT) mice and in mice lacking IL-6 (IL-6KO), IL-17 (IL-17KO), and IFN-γ (GKO) on a C57BL/6 background. Clinical scores of EAU, cytokine levels in supernatants from ocular tissue homogenates, and T helper cell differentiation in lymph nodes in each mouse were examined. To study the roles of Treg cells, EAU was induced in IL-6KO mice treated with anti-CD25 monoclonal antibody (mAb) to deplete Treg cells in vivo. RESULTS. Inflammation was comparable between WT, IL-17KO, and GKO mice but was absent in IL-6KO mice. Th17 and interphotoreceptor retinoid binding protein (IRBP)-specific Th1 cells were increased in GKO and IL-17KO mice, respectively, whereas both populations were reduced in IL-6KO mice. Th1-dominant EAU in IL-17KO mice was suppressed by anti-IL-6R mAb treatment. Treg cell depletion in vivo induced EAU in IL-6KO mice. CONCLUSIONS. After the induction of EAU, IL-6 deficiency resulted in the inhibition of the IRBP-specific Th1 response and enhanced the generation of IRBP-specific Treg cells. Furthermore, Treg was needed to inhibit Th1 responses and ocular inflammation in IL-6KO mice. Protective effects of IL-6 signaling blockade in EAU involve not only Th17 cell inhibition but also IRBP-specific Treg cell promotion.
    Investigative ophthalmology & visual science 02/2011; 52(6):3264-71. DOI:10.1167/iovs.10-6272 · 3.66 Impact Factor
  • Toshio Tanaka, Masashi Narazaki, Tadamitsu Kishimoto
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    ABSTRACT: Interleukin (IL)-6 is a typical cytokine featuring redundancy and pleiotropic activity. It contributes to host defense against pathogens, but dysregulation of IL-6 production plays a significant pathological role in various autoimmune and inflammatory diseases. Because IL-6 blockade was expected to constitute a novel strategy for the treatment of such diseases, tocilizumab, a humanized anti-IL-6 receptor antibody (anti-IL-6RAb), was developed. Clinical trials have demonstrated the efficacy of anti-IL-6RAb for patients with rheumatoid arthritis, Castleman's disease, and juvenile idiopathic arthritis, resulting in approval of this innovative biologic for the treatment of these diseases, and it can be expected to become a novel drug for various other autoimmune and inflammatory diseases. In murine models of autoimmune diseases, anti-IL-6RAb induces Treg and inhibits Th17 and/or Th1 differentiation, indicating that anti-IL-6RAb may be able to repair Th17/Treg imbalance in human diseases as well.
    Annual Review of Pharmacology 01/2011; 52:199-219. DOI:10.1146/annurev-pharmtox-010611-134715 · 18.52 Impact Factor
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    ABSTRACT: IL-6 is a proinflammatory cytokine and its overproduction is implicated in a variety of inflammatory disorders. Recent in vitro analyses suggest that IL-6 is a key cytokine that determines the balance between Foxp3(+) regulatory T cells (Tregs) and Th17 cells. However, it remains unclear whether excessive IL-6 production in vivo alters the development and function of Foxp3(+) Tregs. In this study, we analyzed IL-6 transgenic (Tg) mice in which serum IL-6 levels are constitutively elevated. Interestingly, in IL-6 Tg mice, whereas peripheral lymphoid organs were enlarged, and T cells exhibited activated phenotype, Tregs were not reduced but rather increased compared with wild-type mice. In addition, Tregs from Tg mice normally suppressed proliferation of naive T cells in vitro. Furthermore, Tregs cotransferred with naive CD4 T cells into SCID-IL-6 Tg mice inhibited colitis as successfully as those transferred into control SCID mice. These results indicate that overproduction of IL-6 does not inhibit development or function of Foxp3(+) Tregs in vivo. However, when naive CD4 T cells alone were transferred, Foxp3(+) Tregs retrieved from SCID-IL-6 Tg mice were reduced compared with SCID mice. Moreover, the Helios(-) subpopulation of Foxp3(+) Tregs, recently defined as extrathymic Tregs, was significantly reduced in IL-6 Tg mice compared with wild-type mice. Collectively, these results suggest that IL-6 overproduced in vivo inhibits inducible Treg generation from naive T cells, but does not affect the development and function of natural Tregs.
    The Journal of Immunology 01/2011; 186(1):32-40. DOI:10.4049/jimmunol.0903314 · 5.36 Impact Factor
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    ABSTRACT: The efficacy of anti-tumor necrosis factor monoclonal antibody (anti-TNF mAb) for Crohn's disease (CD) is well established, and anti-interleukin-6 receptor (anti-IL-6R) mAb has also been reported to be effective in CD. It is, however, unclear if the efficacy and mechanisms of both agents are different in CD therapy. Using an adoptive transfer colitis model, we compared the efficacy of anti-IL-6R mAb, anti-TNF mAb, and TNF receptor-Fc fusion protein (TNFR-Fc), and their modes of action on CD4+ T cells. We also investigated the role of Th1 and Th17 cells in colitis using the same model. The histological scores for the anti-IL-6R mAb and anti-TNF mAb groups but not for TNFR-Fc group were much lower than that for the control group, and the score was the lowest for the anti-IL-6R mAb group. The frequency of proliferating CD4+ T cells was reduced in anti-IL-6R mAb and anti-TNF mAb groups, but not in the TNFR-Fc group, whereas the frequency of apoptotic CD4+ T cells was similar in all groups. Anti-IL-6R mAb suppressed the induction of Th17 cells and increased the frequency of lamina propria regulatory T cells, whereas anti-TNF mAb exerted no influence on CD4+ T-cell differentiation. A deficiency in interferon-γ and/or IL-17 in CD4+ T cells reduced the severity of colitis. Our findings suggest that suppression of the proliferation of pathogenic CD4+ T cells is the major mode of action of biological agents for colitis therapy. Anti-IL-6R mAb might have benefits in CD patients with Th17 dominance and impaired Treg frequency.
    Inflammatory Bowel Diseases 01/2011; 17(2):491-502. DOI:10.1002/ibd.21384 · 5.48 Impact Factor
  • Akihiro Kimura, Tetsuji Naka, Tadamitsu Kishimoto
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    ABSTRACT: Naïve T cells are multipotential precursors that differentiate into various effector subsets, such as T helper type 1 (TH1) and TH2 cells, and are characterized by their distinct functions. IL-17-producing T helper (TH17) cell has been recently identified as a new subset of T helper cell and a mediator of inflammation associated with various auto-immune diseases. IL-6 induces the generation of TH17 cells from naïve T cells together with TGF-β and inhibits TGF-β-induced regulatory T (Treg) cells, which suppress adaptive T cell responses and prevent auto-immunity. Because IL-6 plays an important role in directing the balance between Treg and TH17 cell development, controlling IL-6 activities is an effective approach in the treatment of various auto-immune and inflammatory diseases. Here, we review the recent progress in the field of TH17 cell differentiation and regulation and describe the critical functions of IL-6 and TH17 in immunity and diseases.
    12/2010: pages 47-62;
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    ABSTRACT: SSc is an autoimmune disease characterized by fibrosis of the skin and internal organs. Although the aetiology remains uncertain, many reports have suggested that IL-6 is involved in SSc pathogenesis. Tocilizumab, an anti-IL-6 receptor antibody, is an anti-arthritis medicine that works through the blockade of IL-6 functions. To examine the effect of tocilizumab on SSc, we administered tocilizumab to two SSc patients. Two dcSSc patients were administered tocilizumab at 8 mg/kg once a month for 6 months. One patient had pulmonary fibrosis assessed by CT and spirometry, and the other had chronic renal failure caused by scleroderma renal crisis. Their skin condition was monitored with a Vesmeter and the modified Rodnan total skin score (mRTSS). Skin biopsies were obtained before and after the tocilizumab treatment to investigate the histological changes. After tocilizumab treatment, both patients showed softening of the skin with reductions of 50.7 and 55.7% in the total z-score of Vesmeter hardness and 51.9 and 23.0% in the mRTSS, respectively. Histological examination showed thinning of the collagen fibre bundles in the dermis. The creatinine clearance in the patient with chronic renal failure improved from 38 to 55 ml/min. However, the fibrotic changes in the lung in the other patient remained unchanged. In the two cases of SSc that we report here, softening of the skin was observed during the treatment with tocilizumab.
    Rheumatology (Oxford, England) 12/2010; 49(12):2408-12. DOI:10.1093/rheumatology/keq275 · 4.44 Impact Factor
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    ABSTRACT: Although an immunoregulatory role of aryl hydrocarbon receptor (Ahr) has been demonstrated in T cells and macrophages, little is known about its function in dendritic cells (DC). Here, we show that lipopolysaccharide (LPS) and CpG stimulate Ahr expression in bone marrow-derived dendritic cells (BMDC). Furthermore, we found that Ahr is required to induce indoleamine 2,3-dioxygenase (IDO) expression, an immunosuppressive enzyme that catabolizes tryptophan into kynurenine (Kyn) and other metabolites in DC. In the presence of LPS or CpG, Ahr-deficient (Ahr(-/-)) mature BMDC induced immune responses characterized by reduced Kyn and IL-10 production compared with results observed with tolerogenic mature WT BMDC. In a coculture system with LPS- or CpG-stimulated BMDC and naive T cells, Ahr(-/-) BMDC inhibited naive T-cell differentiation into regulatory T (Treg) cells, which likely facilitated Th17 cell development and promoted naive T-cell proliferation. Addition of synthetic L-Kyn to the coculture system skewed the differentiation of naive T cells to Treg cells rather than Th17 cells. Taken together, our results demonstrate a previously unknown negatively regulatory role for Ahr in DC-mediated immunogenesis in the presence of LPS or CpG, which, in turn, alters the Kyn-dependent generation of Treg cells and Th17 cells from naive T cells.
    Proceedings of the National Academy of Sciences 11/2010; 107(46):19961-6. DOI:10.1073/pnas.1014465107 · 9.81 Impact Factor
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    ABSTRACT: The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to cells lacking the IL-6 receptor (IL-6R) when it forms a complex with the soluble IL-6R (sIL-6R) (trans signaling). Here, we have assessed the contribution of this system to the increased resistance of mucosal T cells against apoptosis in Crohn disease (CD), a chronic inflammatory disease of the gastrointestinal tract. A neutralizing antibody against IL-6R suppressed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed gp130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with CD, mucosal T cells showed strong evidence for IL-6 trans signaling, with activation of signal transducer and activator of transcription 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apoptosis, indicating that the IL-6-sIL-6R system mediates the resistance of T cells to apoptosis in CD. These data indicate that a pathway of T-cell activation driven by IL-6-sIL-6R contributes to the perpetuation of chronic intestinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.
    Nature medicine 11/2010; 16(11):1341. DOI:10.1038/nm1110-1341 · 28.05 Impact Factor
  • Akihiro Kimura, Tadamitsu Kishimoto
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    ABSTRACT: Naïve T cells are multipotential precursors that differentiate into various effector subsets, such as T helper type 1 (Th1) and Th2 cells, which are characterized by their distinct functions. The IL-17-producing T helper (Th17) cell has been recently identified as a new subset of the T helper cell and a mediator of inflammation associated with various autoimmune diseases. Although several cytokines participate in Th17 cell development, IL-6 and TGF-β are key factors for the generation of Th17 cells from naïve T cells. On the other hand, IL-6 inhibits TGF-β-induced regulatory T (Treg) cells, which suppress adaptive T cell responses and prevent autoimmunity. Recent studies suggest that it is an effective approach in the treatment of various autoimmune and inflammatory diseases to normalize the balance between Treg and Th17 cell development. Here, we review the discovery of the Th17 subset, its properties and relationship with several autoimmune diseases.
    International immunopharmacology 10/2010; 11(3):319-22. DOI:10.1016/j.intimp.2010.10.004 · 2.71 Impact Factor
  • Cytokine 10/2010; 52(s 1–2):17. DOI:10.1016/j.cyto.2010.07.074 · 2.87 Impact Factor
  • Cytokine 10/2010; 52(s 1–2):23. DOI:10.1016/j.cyto.2010.07.100 · 2.87 Impact Factor
  • Shumpei Yokota, Tadamitsu Kishimoto
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    ABSTRACT: Systemic juvenile idiopathic arthritis (JIA) is a subtype of chronic childhood arthritis of unknown etiology, manifested by long-lasting systemic inflammation and complicated by joint destruction, functional disability and growth impairment. Macrophage activation syndrome is the most devastating complication, which is associated with serious morbidity. IL-6 has been hypothesized to be a pathogenic factor of this disease. The anti-IL-6 receptor monoclonal antibody, tocilizumab, was developed, and we investigated the safety and efficacy of tocilizumab in children with this disorder. The Phase II trial revealed that high-grade fever abruptly subsided and that inflammatory markers were also normalized. The dose of tocilizumab for systemic JIA was revealed to be 8 mg/kg at 2-week intervals. The Phase III trial, a placebo-controlled, double-blind study, indicated that patients in the tocilizumab group had sustained clinical measures of effectiveness and wellbeing, whereas most of those in the placebo group needed rescue treatment. The most common adverse events were symptoms of mild infections and transient increases of alanine aminotransferase. Serious adverse events were anaphylactoid reaction and gastrointestinal hemorrhage. Clinical and laboratory improvement in fever, sickness behavior, C-reactive protein gene expression and chronic inflammatory anemia in children with systemic JIA treated with tocilizumab indicated the possible roles played by IL-6 in this inflammatory disease. Thus, tocilizumab is generally safe and well tolerated. It might be a suitable treatment in the control of this disorder, which has so far been difficult to manage.
    Expert Review of Clinical Immunology 09/2010; 6(5):735-43. DOI:10.1586/eci.10.41 · 3.34 Impact Factor
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    ABSTRACT: The aim of this study was to investigate the effect of anti-mouse IL-6 receptor monoclonal antibody (MR16-1) treatment on CD4 T cell differentiation and compared it to the effect of anti-TNF mAb treatment with using a murine model of experimental autoimmune uveoretinitis (EAU). C57BL/6 mice were immunized with interphotoreceptor retinoid-binding protein (IRBP) to induce ocular inflammation treatment with control IgG or MR16-1 or anti-TNF mAb. Helper T cells differentiation was analyzed during the development of EAU. Immunization with IRBP increased the frequency of Th17 cells rather than Th1 cells in the early stage of EAU. Treatment with MR16-1 on the same day as immunization (day 0) or one day after (day 1) suppressed ocular inflammation in EAU mice. Treatment with MR16-1 on day 0 inhibited the induction of Th17 cells in vivo, and inhibited not only IRBP-responsive Th17 cells but also their Th1 counterparts and induced IRBP-responsive regulatory T (Treg) cells in vitro. The administration of anti-TNF mAb had no significant protective effect in EAU mice. The protective effect of anti-IL-6R mAb treatment, but not anti-TNF mAb treatment on EAU correlated with the inhibition of Th17 differentiation. This finding suggests that IL-6 blockade may have a therapeutic effect on human ocular inflammation which is mediated via mechanisms distinct from those of TNF blockade. IL-6 blockade may thus represent an alternative therapy for patients with ocular inflammation who are refractory to anti-TNF mAb therapy.
    Experimental Eye Research 08/2010; 91(2):162-70. DOI:10.1016/j.exer.2010.04.009 · 3.02 Impact Factor
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    Akihiro Kimura, Tadamitsu Kishimoto
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    ABSTRACT: IL-6 is a pleiotropic cytokine involved in the physiology of virtually every organ system. Recent studies have demonstrated that IL-6 has a very important role in regulating the balance between IL-17-producing Th17 cells and regulatory T cells (Treg). The two T-cell subsets play prominent roles in immune functions: Th17 cell is a key player in the pathogenesis of autoimmune diseases and protection against bacterial infections, while Treg functions to restrain excessive effector T-cell responses. IL-6 induces the development of Th17 cells from naïve T cells together with TGF-beta; in contrast, IL-6 inhibits TGF-beta-induced Treg differentiation. Dysregulation or overproduction of IL-6 leads to autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA), in which Th17 cells are considered to be the primary cause of pathology. Given the critical role of IL-6 in altering the balance between Treg and Th17 cells, controlling IL-6 activities is potentially an effective approach in the treatment of various autoimmune and inflammatory diseases. Here, we review the role of IL-6 in regulating Th17/Treg balance and describe the critical functions of IL-6 and Th17 in immunity and immune-pathology.
    European Journal of Immunology 07/2010; 40(7):1830-5. DOI:10.1002/eji.201040391 · 4.52 Impact Factor
  • Tadamitsu Kishimoto
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    ABSTRACT: In the late 1960s, the essential role of T cells in antibody production was reported. This led to our hypothesis that T-cell-derived soluble factors would have to be involved in the activation of B cells. The factor that induced B cells to produce immunoglobulins was initially named B-cell stimulatory factor-2. In 1986, we successfully cloned the complementary DNA encoding B-cell stimulatory factor-2, now known as IL-6. At the same time, IFN-beta2 and a 26-kDa protein found in fibroblasts were independently cloned and found to be identical to IL-6. Later, a hybridoma/plasmacytoma growth factor and a hepatocyte-stimulating factor were also proven to be the same molecule as IL-6. Now, we know that IL-6 is a pleiotropic cytokine with a wide range of biological activities in immune regulation, hematopoiesis, inflammation and oncogenesis. Since the discovery of IL-6, we have further clarified its activities, the IL-6R system and the IL-6 signal transduction mechanism. On the basis of the findings, a new therapeutic approach to block the actions of IL-6 by use of a humanized anti-IL-6R antibody has been proven to be therapeutically effective for rheumatoid arthritis, systemic juvenile idiopathic arthritis and Castleman's disease. In this review, I discuss the history of IL-6 research as a paradigm of progress from basic science to clinical applications.
    International Immunology 05/2010; 22(5):347-52. DOI:10.1093/intimm/dxq030 · 3.18 Impact Factor
  • The Journal of Rheumatology 05/2010; 37(5):1075-6. DOI:10.3899/jrheum.091185 · 3.17 Impact Factor

Publication Stats

72k Citations
5,411.65 Total Impact Points

Institutions

  • 1977–2014
    • Osaka University
      • • Division of Immune Regulation
      • • Department of Immunoregulation
      • • Graduate School of Frontier Biosciences
      • • Department of Health and Sport Sciences
      • • Division of Cellular and Molecular Biology
      • • Division of Neurosurgery
      • • Immunology Division
      • • Department of Molecular Immunology
      • • Department of Internal Medicine
      Suika, Ōsaka, Japan
  • 1981–2013
    • Osaka City University
      • • Graduate School of Medicine
      • • Department of Cardiovascular Medicine
      • • Department of Urology
      Ōsaka, Ōsaka, Japan
  • 2011
    • Sapienza University of Rome
      • Department of Public Health and Infectious Diseases
      Roma, Latium, Italy
  • 1991–2011
    • Tokyo Institute of Technology
      • • Graduate School of Bioscience and Biotechnology
      • • Department of Bioscience
      • • Department of Biological Sciences
      Edo, Tōkyō, Japan
    • RWTH Aachen University
      Aachen, North Rhine-Westphalia, Germany
  • 2004–2010
    • Yokohama City University
      • Department of Pediatrics
      Yokohama, Kanagawa, Japan
  • 2005
    • Keio University
      Edo, Tōkyō, Japan
  • 2001
    • Duke University
      Durham, North Carolina, United States
    • KAKEN Pharmaceutical Co.,Ltd
      New York City, New York, United States
    • American Society of Hematology
      American Fork, Utah, United States
    • Osaka Prefectural Government
      Ōsaka, Ōsaka, Japan
  • 2000
    • Shinshu University
      Shonai, Nagano, Japan
    • Tokyo Medical and Dental University
      • Department of Molecular Cell Biology
      Edo, Tōkyō, Japan
    • Tokyo Metropolitan University
      • Department of Biological Sciences
      Edo, Tōkyō, Japan
  • 1996–2000
    • Tufts University
      Бостон, Georgia, United States
    • Chinese Academy of Sciences
      Peping, Beijing, China
    • University of Zurich
      • Institut für Experimentelle Immunologie
      Zürich, ZH, Switzerland
    • The University of Tokyo
      • Institute of Medical Science
      Kashiwa, Chiba-ken, Japan
    • University of California, San Diego
      • Department of Medicine
      San Diego, CA, United States
  • 1993–2000
    • Izumi City Hospital
      Ōsaka, Ōsaka, Japan
    • Tokyo Metropolitan Institute of Gerontology
      Edo, Tōkyō, Japan
    • Nara Medical University
      • Department of Internal Medicine
      Nara-shi, Nara, Japan
    • University of Rostock
      Rostock, Mecklenburg-Vorpommern, Germany
    • Indiana University-Purdue University Indianapolis
      • Division of Hematology/Oncology
      Indianapolis, IN, United States
  • 1999
    • Kyoto Prefectural University
      Kioto, Kyōto, Japan
    • Hokkaido University
      • Faculty of Science
      Sapporo, Hokkaidō, Japan
  • 1997–1999
    • Hyogo College of Medicine
      • Department of Biochemistry
      Nishinomiya, Hyōgo, Japan
    • Osaka University of Health and Sport Sciences
      Ōsaka, Ōsaka, Japan
  • 1998
    • Kyoto Prefectural University of Medicine
      Kioto, Kyōto, Japan
    • Toyama Medical and Pharmaceutical University
      Тояма, Toyama, Japan
  • 1995–1998
    • Osaka City General Hospital
      Ōsaka, Ōsaka, Japan
  • 1994–1998
    • Osaka Medical Center and Research Institute for Maternal and Child Health
      Izumi, Ōsaka, Japan
    • University of Tsukuba
      • Institute of Clinical Medicine
      Tsukuba, Ibaraki, Japan
  • 1995–1997
    • Huntington Hospital
      Huntington, New York, United States
  • 1994–1996
    • Kumamoto Municipal Citizens Hospital
      Kumamoto, Kumamoto Prefecture, Japan
  • 1994–1995
    • Tottori University
      • Department of Obstetrics and Gynecology
      TTJ, Tottori, Japan
  • 1993–1995
    • Showa University
      • Department of Biochemistry
      Shinagawa, Tōkyō, Japan
  • 1989–1995
    • Kanazawa University
      • • Department of Obstetrics and Gynecology
      • • Department of Biology
      Kanazawa, Ishikawa, Japan
    • University of Alabama at Birmingham
      • Department of Microbiology
      Birmingham, AL, United States
  • 1990–1994
    • University of California, Los Angeles
      • • Department of Obstetrics and Gynecology
      • • Division of Hematology and Medical Oncology
      Los Ángeles, California, United States
  • 1992
    • National Institute Of Rheumatology And Physiotherapy
      Budapeŝto, Budapest, Hungary
    • Bristol-Myers Squibb
      New York, New York, United States
  • 1991–1992
    • Tosoh Corp.
      Kawasaki Si, Kanagawa, Japan
  • 1990–1992
    • Kagoshima University
      • Department of Internal Medicine
      Kagosima, Kagoshima, Japan
  • 1977–1992
    • Fukushima Medical University
      • Division of Medicine
      Hukusima, Fukushima, Japan
  • 1988–1990
    • AJINOMOTO CO., INC.
      Edo, Tōkyō, Japan
    • University of Freiburg
      • Department of Internal Medicine
      Freiburg, Baden-Württemberg, Germany
    • Osaka Minami Medical Center
      Ōsaka, Ōsaka, Japan
    • New York State
      New York City, New York, United States
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 1987
    • Shionogi & Co., Ltd.
      Ōsaka, Ōsaka, Japan
    • Kumamoto University
      Kumamoto, Kumamoto, Japan
  • 1979–1982
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 1975
    • Osaka Dental University
      Tōkyō, Japan