Details of a Researcher - Yoshimura, Akihiko

Papers - Yoshimura, Akihiko

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Cyclic Adenosine Monophosphate Suppresses the Transcription of Proinflammatory Cytokines via the Phosphorylated c-Fos Protein (DOI

Koga Keiko, Takaesu Giichi, Yoshida Ryoko, Nakaya Mako, Kobayashi Takashi, Kinjyo Ichiko, Yoshimura Akihiko

Immunity 31 ( 1 ) 170 2009.07

ISSN 1074-7613

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The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential

Mori Hiroyuki, Inoki Ken, Masutani Kohsuke, Wakabayashi Yu, Komai Kyoko, Nakagawa Ryusuke, Guan Kun Liang, Yoshimura Akihiko

Biochemical and Biophysical Research Communications 384 ( 4 ) 471 - 475 2009.07

ISSN 0006-291X

Diabetic nephropathy (DN) associated with type 2 diabetes is the most common cause of end-stage renal disease (ESRD) and a serious health issue in the world. Currently, molecular basis for DN has not been established and only limited clinical treatments are effective in abating the progression to ESRD associated with DN. Here we found that diabetic db/db mice which lack the leptin receptor signaling can be used as a model of ESRD associated with DN. We demonstrated that p70S6-kinase was highly activated in mesangial cells in diabetic obese db/db mice. Furthermore, systemic administration of rapamycin, a specific and potent inhibitor of mTOR, markedly ameliorated pathological changes and renal dysfunctions. Moreover, rapamycin treatment shows a significant reduction in fat deposits and attenuates hyperinsulinemia with few side effects. These results indicate that mTOR activation plays a pivotal role in the development of ESRD and that rapamycin could be an effective therapeutic agent for DN. © 2009 Elsevier Inc. All rights reserved.

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Stat1 phosphorylation is a molecular switch of Ras signaling and oncogenesis

Yoshimura Akihiko

Cell Cycle 8 ( 13 ) 1981 - 1982 2009.07

ISSN 1538-4101

The protein content of an adaptor protein, STAP-2 is controlled by E3 ubiquitin ligase Cbl

Sekine Yuichi, Yamamoto Chikako, Ikeda Osamu, Muromoto Ryuta, Nanbo Asuka, Oritani Kenji, Yoshimura Akihiko, Matsuda Tadashi

Biochemical and Biophysical Research Communications 384 ( 2 ) 187 - 192 2009.06

ISSN 0006-291X

Signal transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains pleckstrin and Src homology 2 (SH2)-like domains as well as a YXXQ motif in its C-terminal region. Our previous study in T cells demonstrated that STAP-2 influences FAK protein levels through recruitment of E3 ubiquitin ligase, Cbl, to FAK. In the present study, we found that Cbl directly controls the protein levels and activity of STAP-2. STAP-2 physically interacted with Cbl through its PH and SH2-like domains. Small-interfering RNA-mediated reduction of endogenous Cbl restored STAP-2 protein levels. In contrast, over-expression of Cbl induced STAP-2 degradation. Importantly, Cbl-mediated regulation of STAP-2 protein levels affected Brk/STAP-2-induced STAT3 activation. These results indicate that Cbl regulates STAP-2 protein levels and Brk/STAP-2-mediated STAT3 activation. © 2009 Elsevier Inc. All rights reserved.

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STAP-2 is phosphorylated at tyrosine-250 by Brk and modulates Brk-mediated STAT3 activation

Ikeda Osamu, Miyasaka Yuto, Sekine Yuichi, Mizushima Akihiro, Muromoto Ryuta, Nanbo Asuka, Yoshimura Akihiko, Matsuda Tadashi

Biochemical and Biophysical Research Communications 384 ( 1 ) 71 - 75 2009.06

ISSN 0006-291X

Signal transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains Pleckstrin and Src homology 2 (SH2)-like domains as well as a YXXQ motif in its C-terminal region. STAP-2 is also known as breast tumor kinase (Brk) substrate (BKS). Our previous studies revealed that STAP-2 binds to signal transducer and activator of transcription 3 (STAT3) and STAT5, and regulates the signaling pathways downstream of them. In the present study, we identified tyrosine-250 (Tyr250) in STAP-2 as a major site of phosphorylation by Brk, using a series of STAP-2 YF mutants and anti-phospho-STAP-2 Tyr250 antibody. Furthermore, overexpression of the STAP-2 Y250F mutant protein affected Brk-mediated STAT3 activation. Importantly, small-interfering RNA-mediated reduction of endogenous STAP-2 expression decreased Brk-mediated STAT3 activation. Taken together, our findings demonstrate that STAP-2 is phosphorylated at Tyr250 by Brk, and plays an important role in Brk-mediated STAT3 activation. © 2009 Elsevier Inc. All rights reserved.

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Pulmonary suppressor of cytokine signaling-1 induced by IL-13 regulates allergic asthma phenotype

Fukuyama Satoru, Nakano Takako, Matsumoto Takafumi, Oliver Brian G G, Burgess Janette K., Moriwaki Atsushi, Tanaka Kentaro, Kubo Masato, Hoshino Tomoaki, Tanaka Hiroyuki, McKenzie Andrew N J, Matsumoto Koichiro, Aizawa Hisamichi, Nakanishi Yoichi, Yoshimura Akihiko, Black Judith L., Inoue Hiromasa

American Journal of Respiratory and Critical Care Medicine 179 ( 11 ) 992 - 998 2009.06

ISSN 1073-449X

Rationale: Th2 cytokines play an important role in allergic diseases. These cytokines activate signal transduction pathways, including Janus kinase/signal transducer and activator of transcription (STAT) signaling. Although the suppressor of cytokine signaling (SOCS) family protein, a negative regulator of the Janus kinase/STAT signaling pathway, contributes to helper T cell differentiation during immune responses, the role of SOCS proteins within the structural cells of a target organ has not been clarified in allergy. Objectives: To study the local function of SOCS in the development of asthma. Methods: We used mouse models of IL-13- and ovalbumin (OVA)-induced allergic airway disease. Airway smooth muscle cells were cultured from patients with asthma. Measurements and Main Results: The administration of IL-13 induced not only airway responses but also SOCS1 expression at the local inflammatory site. The up-regulated SOCS1 markedly suppressed IL-13-dependent STAT6 activation and eotaxin expression and subsequently down-regulated IL-13-induced airway inflammatory responses. The inactivation of SOCS1 induced airway hyperresponsiveness after IL-13 treatment even in hyporesponsive C57BL/6 background mice. In an OVA-induced model of allergic airway disease, allergen exposure up-regulated local SOCS1 expression, and the induction of SOCS1 in the airways attenuated allergen-induced airway responses. Inactivation of IL-13 inhibited SOCS1 induction in a model of allergic airway disease. Interestingly, airway smooth muscle cells from individuals with asthma had impaired upregulation of SOCS1 after IL-13 stimulation. Conclusions: SOCS1 induction by IL-13 in airway structural cells is critical to negatively control allergic airway disease.

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Regulation of cytokine signaling by the SOCS and Spred family proteins

Yoshimura Akihiko

Keio Journal of Medicine 58 ( 2 ) 73 - 83 2009.06

ISSN 0022-9717

Various cytokines are involved in the regulation of the immune system and of hematopoiesis. Most cytokines utilize the so-called JAK-STAT pathway, but others activate the Ras-ERK pathway, which is more important than the STAT pathway for the proliferation of hematopoietic cells. Dysregulation of cytokine signaling can cause a variety of diseases, including allergy, inflammation, and cancer. We have identified two important regulator families involved in cytokine signaling: the SOCS proteins and the Spred proteins. Suppressors of cytokine signaling (SOCS) proteins bind to JAK and to certain receptors, thereby suppressing further signaling events. Spred family proteins interact with Ras and Raf, thereby suppressing ERK activation. Studies have shown that SOCS and Spred proteins are key physiological regulators of immunity, hematopoiesis, and angiogenesis. Evidence is also emerging for the involvement of these proteins in human diseases.

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A major lipid raft protein raftlin modulates T cell receptor signaling and enhances Th17-mediated autoimmune responses

Saeki Kazuko, Fukuyama Satoru, Ayada Toranoshin, Nakaya Mako, Aki Daisuke, Takaesu Giichi, Hanada Toshikatsu, Matsumura Yumiko, Kobayashi Takashi, Nakagawa Ryusuke, Yoshimura Akihiko

Journal of Immunology 182 ( 10 ) 5929 - 5937 2009.05

ISSN 0022-1767

The membrane microdomains known as lipid rafts have been shown to act as platforms for the initiation of various receptor signals. Through proteomic analysis, we have identified a novel protein termed Raftlin (raft-linking protein) as a major protein in lipid rafts. To determine the physiological and immunological functions of Raftlin in mammals, we generated Raftlin-deficient mice, as well as Raftlin-transgenic (Tg) mice. Although Raftlin was originally identified in B cells, we observe no severe abnormalities in the B cells of these mice, presumably due to a high expression of Raftlin-homologue (Raftlin-2). T cells, in contrast, expressed a substantial amount of Raftlin but no Raftlin-2. In Raftlin-deficient mice, T cell-dependent Ab production was reduced, and experimental autoimmune encephalomyelitis, a Th17-dependent autoimmune disease model, was ameliorated. In Raftlin-Tg mice, in contrast, Ab production was enhanced and experimental autoimmune encephalomyelitis was more severe. Cytokine production, especially that of IL-17, was reduced in Raftlin-deficient T cells, while it was enhanced in Raftlin-Tg T cells. We found that these changes were associated with the strength of the TCR-mediated signals. Importantly, localization of Lck protein in the lipid rafts was enhanced by Raftlin overexpression and reduced by Raftlin deficiency. These data indicate that Raftlin modulates TCR signals and is necessary for the fine-tuning of T cell-mediated immune responses. Copyright © 2009 by The American Association of Immunologists, Inc.

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Suppression of Sproutys has a therapeutic effect for a mouse model of ischemia by enhancing angiogenesis

Taniguchi Koji, Sasaki Ken Ichiro, Watari Kousuke, Yasukawa Hideo, Imaizumi Tsutomu, Ayada Toranoshin, Okamoto Fuyuki, Ishizaki Takuma, Kato Reiko, Kohno Ri Ichiro, Kimura Hiroshi, Sato Yasufumi, Ono Mayumi, Yonemitsu Yoshikazu, Yoshimura Akihiko

PLoS ONE 4 ( 5 ) 2009.05

Sprouty proteins (Sproutys) inhibit receptor tyrosine kinase signaling and control various aspects of branching morphogenesis. In this study, we examined the physiological function of Sproutys in angiogenesis, using gene targeting and short-hairpin RNA (shRNA) knockdown strategies. Sprouty2 and Sprouty4 double knockout (KO) (DKO) mice were embryonic-lethal around E12.5 due to cardiovascular defects. The number of peripheral blood vessels, but not that of lymphatic vessels, was increased in Sprouty4 KO mice compared with wild-type (WT) mice. Sprouty4 KO mice were more resistant to hind limb ischemia and soft tissue ischemia than WT mice were, because Sprouty4 deficiency causes accelerated neovascularization. Moreover, suppression of Sprouty2 and Sprouty4 expression in vivo by shRNA targeting accelerated angiogenesis and has a therapeutic effect in a mouse model of hind limb ischemia. These data suggest that Sproutys are physiologically important negative regulators of angiogenesis in vivo and novel therapeutic targets for treating peripheral ischemic diseases. Copyright: © 2009 Taniguchi et al.

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An F-box protein, FBXW5, negatively regulates TAK1 MAP3K in the IL-1β signaling pathway

Minoda Yasumasa, Sakurai Hiroaki, Kobayashi Takashi, Yoshimura Akihiko, Takaesu Giichi

Biochemical and Biophysical Research Communications 381 ( 3 ) 412 - 417 2009.04

ISSN 0006-291X

TAK1, a member of the MAP3K family, plays an essential role in activation of JNK/p38 MAPKs and IKK in the IL-1β and TNFα signaling pathway. Upon stimulation, TAK1 is rapidly and transiently activated. While the activation mechanism of TAK1 in these signaling pathways is well characterized, how its activity is terminated still remains unclear. To identify the molecule(s) involved in TAK1 regulation, we performed tandem affinity purification (TAP) in HeLa cells stably expressing TAP-tagged TAK1. FBXW5, an F-box family protein, was identified as a previously unknown component of the IL-1β-induced TAK1 complex. FBXW5 associated with endogenous TAK1 in an IL-1β-dependent manner. Overexpression of FBXW5 inhibited IL-1β-induced activation of JNK/p38 MAPKs and NF-κB as well as phosphorylation of TAK1 on Thr187. Conversely, knockdown of FBXW5 resulted in the prolonged activation of TAK1 upon IL-1β stimulation. These results suggest that FBXW5 negatively regulates TAK1 in the IL-1β signaling pathway. © 2009 Elsevier Inc. All rights reserved.

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Cyclic Adenosine Monophosphate Suppresses the Transcription of Proinflammatory Cytokines via the Phosphorylated c-Fos Protein

Koga Keiko, Takaesu Giichi, Yoshida Ryoko, Nakaya Mako, Kobayashi Takashi, Kinjyo Ichiko, Yoshimura Akihiko

Immunity 30 ( 3 ) 372 - 383 2009.03

ISSN 1074-7613

Intracellular cyclic adenosine monophosphate (cAMP) suppresses innate immunity by inhibiting proinflammatory cytokine production from monocytic cells. Enhanced expression of interleukin-10 (IL-10) has been suggested to be the mechanism of suppression. However, cAMP is still capable of suppressing production of the cytokines TNF-α and IL-12 in IL-10-deficient dendritic cells (DCs). Here, we demonstrated that the transcription factor c-Fos was responsible for the cAMP-mediated suppression of inflammatory cytokine production. c-Fos accumulated at high amounts in response to cAMP and lipopolysaccharide (LPS). Overexpression of c-Fos suppressed LPS-induced cytokine production, whereas cAMP-mediated suppression of TNF-α and IL-12 was impaired in Fos^-/- DCs or in RAW264.7 cells treated with c-Fos siRNA. c-Fos physically interacted with p65 protein and reduced the recruitment of p65 to the Tnf promoter. Multiple sites of c-Fos were phosphorylated by the IKKβ protein. Thus, we propose that c-Fos is a substrate of IKKβ and is responsible for the immunosuppressive effect of cAMP. © 2009 Elsevier Inc. All rights reserved.

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TRAF6 is required for generation of the B-1a B cell compartment as well as T cell-dependent and-independent humoral immune responses

Kobayashi Takashi, Kim Tae Soo, Jacob Anand, Walsh Matthew C., Kadono Yuho, Fuentes-Pananá Ezequiel, Yoshioka Tomoko, Yoshimura Akihiko, Yamamoto Masahiro, Kaisho Tsuneyasu, Akira Shizuo, Monroe John G., Choi Yongwon

PLoS ONE 4 ( 3 ) 2009.03

TNF receptor superfamily members, such as CD40 and the Toll-like receptors (TLRs), regulate many aspects of B cell differentiation and activation. TRAF6 is an intracellular signaling adaptor molecule for these receptors, but its role in B cells has not been clarified by previous genetic approaches, as the systemic deletion of the TRAF6 gene results in perinatal lethality. Here we show that B cell-specific TRAF6 deficiency results in a reduced number of mature B cells in the bone marrow and spleen. Optimal T cell-dependent (TD) antigen responses, as characterized by isotype switching and long-lived plasma cell generation, are also impaired in B cell-specific TRAF6-deficient mice. B cell-specific TRAF6-deficient mice also exhibit lower levels of serum IgM and IgG2b and defective antigen-specific IgM production in response to T cell-independent (TI) antigens. Unexpectedly, TRAF6-deficient B cell progenitors are unable to generate CD5+ B-1 cells. These results reveal critical roles for TRAF6 in TD and TI humoral immune responses and in inductive fate decisions necessary to generate the B-1 B cell compartment. © 2009 Kobayashi et al.

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PIAS3 negatively regulates RANKL-mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts

Hikata Tomohiro, Takaishi Hironari, Jiro Takito, Hakozaki Akihiro, Furukawa Mitsuru, Uchikawa Shinichi, Kimura Tokuhiro, Okada Yasunori, Matsumoto Masahito, Yoshimura Akihiko, Nishimura Riko, Reddy Sakamuri V., Asahara Hiroshi, Toyama Yoshiaki

Blood 113 ( 10 ) 2202 - 2212 2009.03

ISSN 0006-4971

Cytokine signaling via various transcription factors regulates receptor activator of nuclear factor (NF)-κB ligand (RANKL)-mediated osteoclast differentiation from monocyte/macrophage lineage cells involved in propagation and resolution of inflammatory bone destruction. Protein inhibitor of activated STAT3 (PIAS3) was initially identified as a molecule that inhibits DNA binding of STAT3 and regulates many transcription factors through distinct mechanisms. To analyze PIAS3 function in osteoclasts in vivo, we have generated transgenic mice in which PIAS3 is specifically expressed in the osteoclast lineage using the tartrate-resistant acid phosphatase (TRAP) gene promoter. PIAS3 transgenic mice showed an osteopetrotic phenotype due to impairment of osteoclast differentiation. Overexpression of PIAS3 in RAW264.7 cells suppressed RANKL-induced osteoclastogenesis by inhibiting the expression of c-Fos and NFATc1. Interestingly, PIAS3 inhibits the transcriptional activity of microphthalmia-associated transcription factor (MITF) independent of sumoylation. Down-regulation of PIAS3 markedly enhances RANKL-mediated osteoclastogenesis in RAW264.7 cells. Furthermore, overexpression of PIAS3 in mouse primary osteoblast (POB), down-regulates RANKL expression induced by interleukin-6 (IL-6) cytokine family, and inhibits osteoclast formation from bone marrow macrophages (BMMs) in vitro coculture system. Down-regulation of PIAS3 leads to the accelerated expression of RANKL in POB stimulated with IL-6 and soluble IL-6 receptor (sIL-6R). Taken together, our results clearly indicate that PIAS3 negatively regulates RANKL-mediated osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblasts. © 2009 by The American Society of Hematology.

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Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4,5-biphosphate hydrolysis

Ayada T., Taniguchi K., Okamoto F., Kato R., Komune S., Takaesu G., Yoshimura A.

Oncogene 28 ( 8 ) 1076 - 1088 2009.02

ISSN 0950-9232

Sproutys have been shown to negatively regulate growth factor-induced extracellular signal-regulated kinase (ERK) activation, and suggested to be an anti-oncogene. However, molecular mechanism of the suppression has not yet been clarified completely. Sprouty4 inhibits vascular endothelial growth factor (VEGF)-A-induced ERK activation, but not VEGF-C-induced ERK activation. It has been shown that VEGF-A-mediated ERK activation is strongly dependent on protein kinase C (PKC), whereas that by VEGF-C is dependent on Ras. This suggests that Sprouty4 inhibits the PKC pathway more specifically than the Ras pathway. In this study, we confirmed that Sprouty4 suppressed various signals downstream of PKC, such as phosphorylation of MARCKS and protein kinase D (PKD), as well as PKC-dependent nuclear factor (NF)-κB activation. Furthermore, Sprouty4 suppressed upstream signals of PKC, such as Ca²⁺ mobilization, phosphatidylinositol 4,5-biphosphate (PIP₂) breakdown and inositol 1,4,5-triphosphate (IP₃) production in response to VEGF-A. Those effects were dependent on the C-terminal cysteine-rich region, but not on the N-terminal region of Sprouty4, which is critical for the suppression of fibroblast growth factor (FGF)-mediated ERK activation. Sprouty4 overexpression or deletion of the Sprouty4 gene did not affect phospholipase C (PLC) γ-1 activation, which is an enzyme that catalyzes PIP₂ hydrolysis. Moreover, Sprouty4 inhibited not only VEGF-A-mediated PIP₂ hydrolysis but also inhibited the lysophosphatidic acid (LPA)-induced PIP₂ breakdown that is catalyzed by PLCβ/ε activated by G-protein coupled receptor (GPCR). Taken together, Sprouty4 has broader suppression activity for various stimuli than previously thought; it may function as an inhibitor for various types of PLC-dependent signaling as well as for ERK activation. © 2009 Macmillan Publishers Limited All rights reserved.

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Foxp3-Dependent MicroRNA155 Confers Competitive Fitness to Regulatory T Cells by Targeting SOCS1 Protein

Lu Li Fan, Thai To Ha, Calado Dinis Pedro, Chaudhry Ashutosh, Kubo Masato, Tanaka Kentaro, Loeb Gabriel B., Lee Hana, Yoshimura Akihiko, Rajewsky Klaus, Rudensky Alexander Y.

Immunity 30 ( 1 ) 80 - 91 2009.01

ISSN 1074-7613

Foxp3⁺ regulatory T (Treg) cells limit pathogenic immune responses to self-antigens and foreign antigens. An essential role for microRNA (miRNA) in the maintenance and function of Treg cells, revealed by the Treg cell-specific Dicer ablation, raised a question as to a specific miRNA contribution. We found that Foxp3 controlled the elevated miR155 expression required for maintaining Treg cell proliferative activity and numbers under nonlymphopenic conditions. Moreover, miR155 deficiency in Treg cells resulted in increased suppressor of cytokine signaling 1 (SOCS1) expression accompanied by impaired activation of signal transducer and activator of transcription 5 (STAT5) transcription factor in response to limiting amounts of interleukin-2. Our studies suggest that Foxp3-dependent regulation of miR155 maintains competitive fitness of Treg cell subsets by targeting SOCS1, and they provide experimental support for a proposed role for miRNAs in ensuring the robustness of cellular phenotypes. © 2009 Elsevier Inc. All rights reserved.

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Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome

Messiaen Ludwine, Yao Suxia, Brems Hilde, Callens Tom, Sathienkijkanchai Achara, Denayer Ellen, Spencer Emily, Arn Pamela, Babovic-Vuksanovic Dusica, Bay Carolyn, Bobele Gary, Cohen Bruce H., Escobar Luis, Eunpu Deborah, Grebe Theresa, Greenstein Robert, Hachen Rachel, Irons Mira, Kronn David, Lemire Edmond, Leppig Kathleen, Lim Cynthia, McDonald Marie, Narayanan Vinodh, Pearn Amy, Pedersen Robert, Powell Berkley, Shapiro Lawrence R., Skidmore David, Tegay David, Thiese Heidi, Zackai Elaine H., Vijzelaar Raymon, Taniguchi Koji, Ayada Toranoshin, Okamoto Fuyuki, Yoshimura Akihiko, Parret Annabel, Korf Bruce, Legius Eric

JAMA - Journal of the American Medical Association 302 ( 19 ) 2111 - 2118 2009

ISSN 0098-7484

Context: Autosomal dominant inactivating sprouty-related EVH1 domain-containing protein 1 (SPRED1) mutations have recently been described in individuals presenting mainly with café au lait macules (CALMs), axillary freckling, and macrocephaly. The extent of the clinical spectrum of this new disorder needs further delineation. Objective: To determine the frequency, mutational spectrum, and phenotype of neurofibromatosis type 1-like syndrome (NFLS) in a large cohort of patients. Design, Setting, and Participants: In a cross-sectional study, 23 unrelated probands carrying a SPRED1 mutation identified through clinical testing participated with their families in a genotype-phenotype study (2007-2008). In a second cross-sectional study, 1318 unrelated anonymous samples collected in 2003-2007 from patients with a broad range of signs typically found in neurofibromatosis type 1 (NF1) but no detectable NF1 germline mutation underwent SPRED1 mutation analysis. Main Outcome Measures: Comparison of aggregated clinical features in patients with or without a SPRED1 or NF1 mutation. Functional assays were used to evaluate the pathogenicity of missense mutations. Results: Among 42 SPRED1-positive individuals from the clinical cohort, 20 (48%; 95% confidence interval [CI], 32%-64%) fulfilled National Institutes of Health (NIH) NF1 diagnostic criteria based on the presence of more than 5 CALMs with or without freckling or an NF1-compatible family history. None of the 42 SPRED1-positive individuals (0%; 95% CI, 0%-7%) had discrete cutaneous or plexiform neurofibromas, typical NF1 osseous lesions, or symptomatic optic pathway gliomas. In the anonymous cohort of 1318 individuals, 34 different SPRED1 mutations in 43 probands were identified: 27 pathogenic mutations in 34 probands and 7 probable nonpathogenic missense mutations in 9 probands. Of 94 probands with familial CALMs with or without freckling and no other NF1 features, 69 (73%; 95% CI, 63%-80%) had an NF1 mutation and 18 (19%; 95% CI, 12%-29%) had a pathogenic SPRED1 mutation. In the anonymous cohort, 1.9% (95% CI, 1.2%-2.9%) of individuals with the clinical diagnosis of NF1 according to the NIH criteria had NFLS. Conclusions: A high SPRED1 mutation detection rate was found in NF1 mutation-negative families with an autosomal dominant phenotype of CALMs with or without freckling and no other NF1 features. Among individuals in this study, NFLS was not associated with the peripheral and central nervous system tumors seen in NF1. ©2009 American Medical Association. All rights reserved.

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Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis

Yoshimura Takeru, Sonoda Koh Hei, Ohguro Nobuyuki, Ohsugi Yoshiyuki, Ishibashi Tatsuro, Cua Daniel J., Kobayashi Takashi, Yoshida Hiroki, Yoshimura Akihiko

Rheumatology 48 ( 4 ) 347 - 354 2009

ISSN 1462-0324

Objectives. Human endogenous uveitis is one of the sight-threatening diseases associated with variety of systemic disorders, such as Behcet's disease and sarcoidosis. Recently, biosynthesized antibodies against inflammatory cytokines have been recognized to be useful to control the regional inflammation. In this study, we focused on the possibility of IL-6-based biological therapies for endogenous uveitis. We initially confirmed the significant increase of several inflammatory soluble factors including IL-6 in the vitreous fluids from refractory/chronic engogenous uveitis patients. Methods. To investigate the role of IL-6 in the formation of refractory ocular inflammation, we used the mouse experimental autoimmune uveitis (EAU) model. Both IL-6 and IL-23 are required for the development of IL-17-producing helper T subset (Th17) from naïve CD4⁺T cells. Results. In the EAU model, neither IL-6-deficient mice nor IL-23-deficient mice could induce Th17 cells and the EAU score was decreased in these mice in the entire time course. We also confirmed that systemic administration of anti-IL-6 receptor antibody ameliorates EAU by suppressing both systemic and regional Th17 responses. Conclusions. IL-6 is responsible for causing ocular inflammation, and it is, at least partially, due to IL-6-dependent Th17 differentiation. IL-6 may be a target for therapy of refractory endogenous uveitis in humans. © The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

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IFN-γ expression in CD8⁺ T cells regulated by IL-6 signal is involved in superantigen-mediated CD4⁺ T cell death

Atsumi Toru, Sato Masae, Kamimura Daisuke, Moroi Arisa, Iwakura Yoichiro, Betz Ulrich A K, Yoshimura Akihiko, Nishihara Mika, Hirano Toshio, Murakami Masaaki

International Immunology 21 ( 1 ) 73 - 80 2009

ISSN 0953-8178

Infection with pathogens containing superantigens (Sags) can result in massive excessive CD4⁺ T cell activation and death in such conditions as toxic shock, food poisoning and autoimmune diseases. We here showed how enhancement of IL-6 signaling suppresses Sag-mediated activated CD4⁺ T cell death. Sag-induced CD4⁺ T cell death increased in IL-6 knockout (KO) mice, whereas it decreased in mice characterized by enhanced IL-6-gp130-STAT3 signaling. The serum concentration of IFN-γ was inversely correlated with the magnitude of IL-6 signaling, and IFN-γ deficiency inhibited Sag-induced activated CD4⁺ T cell death, suggesting that IL-6 suppresses CD4⁺ T cell death via IFN-γ expression. Interestingly, depletion of activated CD8⁺ T cells inhibited Sag-mediated increases in IFN-γ expression in IL-6 KO mice as well as the augmented CD4⁺ T cell death. The results demonstrate that IL-6-gp130-STAT3 signaling in activated CD8⁺ T cells contributes to Sag-induced CD4⁺ T cell death via IFN-γ expression, highlighting this signaling axis in CD8⁺ T cells as a potential therapeutic target for Sag-related syndromes. © The Japanese Society for Immunology. 2008. All rights reserved.

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Silencing of SOCS1 in macrophages suppresses tumor development by enhancing antitumor inflammation

Hashimoto Masayuki, Ayada Toranoshin, Kinjyo Ichiko, Hiwatashi Kiyokazu, Yoshida Hideyuki, Okada Yasunori, Kobayashi Takashi, Yoshimura Akihiko

Cancer Science 100 ( 4 ) 730 - 736 2009

ISSN 1347-9032

Inflammation has been shown to contribute to both tumor development and antitumor immunity. However, conditions determining these opposing effects are not well understood. Suppressor of cytokine signaling 1 (SOCS1) has been shown to play an important role in regulating inflammation and tumor development. It has been reported that silencing of SOCS1 gene in dendritic cells potentiates antitumor immunity, while SOCS1-deficiency in whole organs except for T and B cells enhances inflammation-mediated colon tumor development. To determine which types of cells are important for the suppression of tumor development by SOCS1-deficiency, we employed the conditional knockout strategy. SOCS1 gene was deleted in macrophages and neutrophils by crossing SOCS1-flox/ flox mice with LysM-cre mice. Resulting conditional knockout (cKO) mice showed enhanced sensitivity to endotoxin shock. SOCS1-cKO mice survived much longer than wild-type mice after B16 melanoma transplantation. Colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH) plus dextran sulfate sodium (DSS) was also reduced in SOCS1-cKO mice. SOCS1-deficiency in monocytic cells enhanced tumor-killing activity of macrophages and tumor-specific cytotoxic T cell activity. These results suggest that inflammation induced by SOCS1-deficiency in monocytes potentiates antitumor immune responses rather than tumor-promoting inflammation. © 2009 Japanese Cancer Association.

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Gfi1 negatively regulates T_h17 differentiation by inhibiting RORγt activity

Ichiyama Kenji, Hashimoto Masayuki, Sekiya Takashi, Nakagawa Ryusuke, Wakabayashi Yu, Sugiyama Yuki, Komai Kyoko, Saba Ingrid, Möröy Tarik, Yoshimura Akihiko

International Immunology 21 ( 7 ) 881 - 889 2009

ISSN 0953-8178

T_h cells have long been divided into two subsets, T_h1 and T_h2; however, recently, T_h17 and inducible regulatory T (iTreg) cells were identified as new T_hcell subsets. Although T_h1- and T_h 2-polarizing cytokines have been shown to suppress T_h17 and iTreg development, transcriptional regulation of T_h17 and iTreg differentiation by cytokines remains to be clarified. In this study, we found that expression of the growth factor independent 1 (Gfi1) gene, which has been implicated in T_h2 development, was repressed in T_h17 and iTreg cells compared with T_h 1 and T_h2 lineages. Gfi1 expression was enhanced by the IFN-γ/STAT1 and IL-4/STAT6 pathways, whereas it was repressed by the transforming growth factor-β1 stimulation at the promoter level. Over-expression of Gfi1 strongly reduced IL-17A transcription in the EL4 T cell line, as well as in primary T cells. This was due to the blockade of recruitment of retinoid-related orphan receptor γt to the IL-17A promoter. In contrast, IL-17A expression was significantly enhanced in Gfi1-deficient T cells under T_h17-promoting differentiation conditions as compared with wild-type T cells. In contrast, the impacts of Gfi1 in iTregs were not as strong as in T_h17 cells. Taken together, these data strongly suggest that Gfi1 is a negative regulator of T_h17 differentiation, which represents a novel mechanism for the regulation of T_h17 development by cytokines. © The Japanese Society for Immunology. 2009. All rights reserved.

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