Papers - Yoshimura, Akihiko

Neuronal suppressor of cytokine signaling-3 deficiency enhances hypothalamic leptin-dependent phosphatidylinositol 3-kinase signaling

Metlakunta Anantha S., Sahu Maitrayee, Yasukawa Hideo, Dhillon Sandeep S., Belsham Denise D., Yoshimura Akihiko, Sahu Abhiram

American Journal of Physiology - Regulatory Integrative and Comparative Physiology 300 ( 5 )  2011.05

ISSN  0363-6119

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<p>Suppressor of cytokine signaling-3 (SOCS3) is thought to be involved in the development of central leptin resistance and obesity by inhibiting STAT3 pathway. Because phosphatidylinositol 3-kinase (PI3K) pathway plays an important role in transducing leptin action in the hypothalamus, we examined whether SOCS3 exerted an inhibition on this pathway. We first determined whether leptin sensitivity in the hypothalamic PI3K pathway was increased in brain-specific Socs3-deficient (NesKO) mice. In NesKO mice, hypothalamic insulin receptor substrate-1 (IRS1)-associated PI3K activity was significantly increased at 30 min and remained elevated up to 2 h after leptin intraperitoneal injection, but in wild-type (WT) littermates, the significant increase was only at 30 min. Hypothalamic p-STAT3 levels were increased up to 5 h in NesKO as opposed to 2 h in WT mice. In food-restricted WT mice with reduced body weight, leptin increased hypothalamic PI3K activity only at 30 min, and p-STAT3 levels at 30 -120 min postinjection. These results suggest increased leptin sensitivity in both PI3K and STAT3 pathways in the hypothalamus of NesKO mice, which was not due to a lean phenotype. In the next experiment with a clonal hypothalamic neuronal cell line expressing proopiomelanocortin, we observed that whereas leptin significantly increased IRS1-associated PI3K activity and p-JAK2 levels in cells transfected with control vector, it failed to do so in SOCS3- overexpressed cells. Altogether, these results imply a SOCS3 inhibition of the PI3K pathway of leptin signaling in the hypothalamus, which may be one of the mechanisms behind the development of central leptin resistance and obesity. © 2011 the American Physiological Society.</p>

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Suppressors of cytokine signaling (SOCS) proteins and JAK/STAT pathways

Tamiya Taiga, Kashiwagi Ikko, Takahashi Reiko, Yasukawa Hideo, Yoshimura Akihiko

Arteriosclerosis, Thrombosis, and Vascular Biology 31 ( 5 ) 980 - 985 2011.05

ISSN  1079-5642

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<p>Various cytokines are involved in the regulation of the immune system and inflammation. Dysregulation of cytokine signaling can cause a variety of diseases, including allergy, autoimmune diseases, inflammation, and cancer. Most cytokines use the so-called janus kinase/signal transducer and activator of transcription pathway, and this pathway is negatively regulated by suppressors of cytokine signaling (SOCS) proteins. SOCS proteins bind to janus kinase and to certain cytokine receptors and signaling molecules, thereby suppressing further signaling events. Studies have shown that SOCS proteins are key physiological regulators of inflammation. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of adaptive immunity. Copyright © 2011 American Heart Association. All rights reserved.</p>

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Stat3/Socs3 Activation by IL-6 Transsignaling Promotes Progression of Pancreatic Intraepithelial Neoplasia and Development of Pancreatic Cancer

Lesina Marina, Kurkowski Magdalena U., Ludes Katharina, Rose-John Stefan, Treiber Matthias, Klöppel Günter, Yoshimura Akihiko, Reindl Wolfgang, Sipos Bence, Akira Shizuo, Schmid Roland M., Algül Hana

Cancer Cell 19 ( 4 ) 456 - 469 2011.04

ISSN  1535-6108

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<p>Physiological levels of Kras^G12D are sufficient to induce pancreatic intraepithelial neoplasias (PanINs); the mechanisms that drive PanIN progression are unknown. Here, we establish that, in addition to oncogenic Kras^G12D, IL-6 transsignaling-dependent activation of Stat3/Socs3 is required to promote PanIN progression and pancreatic ductal adenocarcinoma (PDAC). Myeloid compartment induces Stat3 activation by secreting IL-6; consequently, IL-6 transsignaling activates Stat3 in the pancreas. Using genetic tools, we show that inactivation of IL-6 transsignaling or Stat3 inhibits PanIN progression and reduces the development of PDAC. Aberrant activation of Stat3 through homozygous deletion of Socs3 in the pancreas accelerates PanIN progression and PDAC development. Our data describe the involvement of IL-6 transsignaling/Stat3/Socs3 in PanIN progression and PDAC development. © 2011 Elsevier Inc.</p>

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Stat3/Socs3 Activation by IL-6 Transsignaling Promotes Progression of Pancreatic Intraepithelial Neoplasia and Development of Pancreatic Cancer

Lesina Marina, Kurkowski Magdalena U., Ludes Katharina, Rose-John Stefan, Treiber Matthias, Klöppel Günter, Yoshimura Akihiko, Reindl Wolfgang, Sipos Bence, Akira Shizuo, Schmid Roland M., Algül Hana

Cancer Cell 19 ( 4 ) 456 - 469 2011.04

ISSN  1535-6108

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<p>Physiological levels of Kras^G12D are sufficient to induce pancreatic intraepithelial neoplasias (PanINs); the mechanisms that drive PanIN progression are unknown. Here, we establish that, in addition to oncogenic Kras^G12D, IL-6 transsignaling-dependent activation of Stat3/Socs3 is required to promote PanIN progression and pancreatic ductal adenocarcinoma (PDAC). Myeloid compartment induces Stat3 activation by secreting IL-6; consequently, IL-6 transsignaling activates Stat3 in the pancreas. Using genetic tools, we show that inactivation of IL-6 transsignaling or Stat3 inhibits PanIN progression and reduces the development of PDAC. Aberrant activation of Stat3 through homozygous deletion of Socs3 in the pancreas accelerates PanIN progression and PDAC development. Our data describe the involvement of IL-6 transsignaling/Stat3/Socs3 in PanIN progression and PDAC development. © 2011 Elsevier Inc.</p>

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T cell treatment with small interfering RNA for suppressor of cytokine signaling 3 modulates allergic airway responses in a murine model of asthma

Moriwaki Atsushi, Inoue Hiromasa, Nakano Takako, Matsunaga Yuko, Matsuno Yukiko, Matsumoto Takafumi, Fukuyama Satoru, Kan-o Keiko, Matsumoto Koichiro, Tsuda-Eguchi Miyuki, Nagakubo Daisuke, Yoshie Osamu, Yoshimura Akihiko, Kubo Masato, Nakanishi Yoichi

American Journal of Respiratory Cell and Molecular Biology 44 ( 4 ) 448 - 455 2011.04

ISSN  1044-1549

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<p>CD4+ T cells, particularly T helper (Th) 2 cells, play a pivotal role in the pathophysiology of allergic asthma. Suppressor of cytokine signaling (SOCS) proteins control the balance of CD4⁺ T cell differentiation. Mice that lack SOCS3 in T cells by crossing SOCS3-floxed mice with Lck-Cre-transgenic mice have reduced allergen-induced eosinophilia in the airways. Here, we studied the effects of SOCS3 silencing with small interfering (si) RNA in primary CD4⁺ T cells on Th2 cell differentiation and on asthmatic responses in mice. Th2 cells were generated from ovalbumin (OVA)-specific T cell receptor-transgenic mice in vitroandtransferred into recipient mice. Transfection of SOCS3-specific siRNA attenuated Th2 response in vitro. Adoptive transfer of SOCS3-siRNAT cells exhibited markedly suppressed airway hyperresponsiveness and eosinophilia after OVA challenge, with a concomitant decrease in OVA-specific CD4⁺ T cell accumulation in the airways. To investigate the mechanism of this impaired CD4⁺ T cell accumulation, we inactivated SOCS3 of T cells by crossing SOCS3-floxed (SOCS3 ^flox/flox) mice with CD4-Cre transgenic mice. CD4-Cre x SOCS3 ^flox/flox mice exhibited fewer IL-4-producing cells and more reduced eosinophil infiltration in bronchoalveolar lavage fluids than control mice in a model of OVA-induced asthma. Expression of CCR3 and CCR4 in CD4⁺ T cells was decreased in CD4-Cre x SOCS3^flox/flox mice. CCR4 expression was also decreased in CD4⁺ T cells after transfer of SOCS3 siRNA-treated T cells. These findings suggest that the therapeutic modulation of SOCS3 expression in CD4⁺ T cells might be effective in preventing the development of allergic asthma. Copyright © 2011 American Thoracic Society.</p>

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T cell treatment with small interfering RNA for suppressor of cytokine signaling 3 modulates allergic airway responses in a murine model of asthma

Moriwaki Atsushi, Inoue Hiromasa, Nakano Takako, Matsunaga Yuko, Matsuno Yukiko, Matsumoto Takafumi, Fukuyama Satoru, Kan-o Keiko, Matsumoto Koichiro, Tsuda-Eguchi Miyuki, Nagakubo Daisuke, Yoshie Osamu, Yoshimura Akihiko, Kubo Masato, Nakanishi Yoichi

American Journal of Respiratory Cell and Molecular Biology 44 ( 4 ) 448 - 455 2011.04

ISSN  1044-1549

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<p>CD4+ T cells, particularly T helper (Th) 2 cells, play a pivotal role in the pathophysiology of allergic asthma. Suppressor of cytokine signaling (SOCS) proteins control the balance of CD4⁺ T cell differentiation. Mice that lack SOCS3 in T cells by crossing SOCS3-floxed mice with Lck-Cre-transgenic mice have reduced allergen-induced eosinophilia in the airways. Here, we studied the effects of SOCS3 silencing with small interfering (si) RNA in primary CD4⁺ T cells on Th2 cell differentiation and on asthmatic responses in mice. Th2 cells were generated from ovalbumin (OVA)-specific T cell receptor-transgenic mice in vitroandtransferred into recipient mice. Transfection of SOCS3-specific siRNA attenuated Th2 response in vitro. Adoptive transfer of SOCS3-siRNAT cells exhibited markedly suppressed airway hyperresponsiveness and eosinophilia after OVA challenge, with a concomitant decrease in OVA-specific CD4⁺ T cell accumulation in the airways. To investigate the mechanism of this impaired CD4⁺ T cell accumulation, we inactivated SOCS3 of T cells by crossing SOCS3-floxed (SOCS3 ^flox/flox) mice with CD4-Cre transgenic mice. CD4-Cre x SOCS3 ^flox/flox mice exhibited fewer IL-4-producing cells and more reduced eosinophil infiltration in bronchoalveolar lavage fluids than control mice in a model of OVA-induced asthma. Expression of CCR3 and CCR4 in CD4⁺ T cells was decreased in CD4-Cre x SOCS3^flox/flox mice. CCR4 expression was also decreased in CD4⁺ T cells after transfer of SOCS3 siRNA-treated T cells. These findings suggest that the therapeutic modulation of SOCS3 expression in CD4⁺ T cells might be effective in preventing the development of allergic asthma. Copyright © 2011 American Thoracic Society.</p>

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Involvement of STAP-2 in Brk-mediated phosphorylation and activation of STAT5 in breast cancer cells

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

Cancer Science 102 ( 4 ) 756 - 761 2011.04

ISSN  1347-9032

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<p>Signal-transducing adaptor protein (STAP)-2 is a recently identified adaptor protein that contains Pleckstrin homology and Src homology 2-like domains, and is also known to be a substrate of breast tumor kinase (Brk). In a previous study, we found that STAP-2 upregulated Brk-mediated activation of signal transducer and activator of transcription (STAT) 3 in breast cancer cells. Here, we examined the involvement of STAP-2 in Brk-mediated STAT5 activation in breast cancer cells. Ectopic expression of STAP-2 induced Brk-mediated transcriptional activity of STAT5. Furthermore, STAP-2-knockdown in T47D breast cancer cells induced a marked decrease in proliferation that was as strong as that after Brk- or STAT5b-knockdown. Regarding the mechanism, the Pleckstrin homology domain of STAP-2 is likely to participate in the process by which Brk phosphorylates and activates STAT5. Taken together, our findings provide insights toward the development of novel therapeutic strategies as well as novel prognostic values in breast carcinomas. © 2011 Japanese Cancer Association.</p>

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Involvement of STAP-2 in Brk-mediated phosphorylation and activation of STAT5 in breast cancer cells

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

Cancer Science 102 ( 4 ) 756 - 761 2011.04

ISSN  1347-9032

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<p>Signal-transducing adaptor protein (STAP)-2 is a recently identified adaptor protein that contains Pleckstrin homology and Src homology 2-like domains, and is also known to be a substrate of breast tumor kinase (Brk). In a previous study, we found that STAP-2 upregulated Brk-mediated activation of signal transducer and activator of transcription (STAT) 3 in breast cancer cells. Here, we examined the involvement of STAP-2 in Brk-mediated STAT5 activation in breast cancer cells. Ectopic expression of STAP-2 induced Brk-mediated transcriptional activity of STAT5. Furthermore, STAP-2-knockdown in T47D breast cancer cells induced a marked decrease in proliferation that was as strong as that after Brk- or STAT5b-knockdown. Regarding the mechanism, the Pleckstrin homology domain of STAP-2 is likely to participate in the process by which Brk phosphorylates and activates STAT5. Taken together, our findings provide insights toward the development of novel therapeutic strategies as well as novel prognostic values in breast carcinomas. © 2011 Japanese Cancer Association.</p>

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Raftlin is involved in the nucleocapture complex to induce poly(I

Watanabe Ayako, Tatematsu Megumi, Saeki Kazuko, Shibata Sachiko, Shime Hiroaki, Yoshimura Akihiko, Obuse Chikashi, Seya Tsukasa, Matsumoto Misako

Journal of Biological Chemistry 286 ( 12 ) 10702 - 10711 2011.03

ISSN  0021-9258

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<p>The double-stranded RNA analog, poly(I:C), extracellularly activates both the endosomal Toll-like receptor (TLR) 3 and the cytoplasmic RNA helicase, melanoma differentiation-associated gene 5, leading to the production of type I interferons (IFNs) and inflammatory cytokines. The mechanism by which extracellular poly(I:C) is delivered to TLR3-positive organelles and the cytoplasm remains to be elucidated. Here, we show that the cytoplasmic lipid raft protein, Raftlin, is essential for poly(I:C) cellular uptake in human myeloid dendritic cells and epithelial cells. When Raftlin was silenced, poly(I:C) failed to enter cells and induction of IFN-β production was inhibited. In addition, cellular uptake of B-type oligodeoxynucleotide that shares its uptake receptor with poly(I:C) was suppressed in Raftlin knockdown cells. Upon poly(I:C) stimulation, Raftlin was translocated from the cytoplasm to the plasma membrane where it colocalized with poly(I:C), and thereafter moved to TLR3-positive endosomes. Thus, Raftlin cooperates with the uptake receptor to mediate cell entry of poly(I:C), which is critical for activation of TLR3. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.</p>

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Raftlin is involved in the nucleocapture complex to induce poly(I

Watanabe Ayako, Tatematsu Megumi, Saeki Kazuko, Shibata Sachiko, Shime Hiroaki, Yoshimura Akihiko, Obuse Chikashi, Seya Tsukasa, Matsumoto Misako

Journal of Biological Chemistry 286 ( 12 ) 10702 - 10711 2011.03

ISSN  0021-9258

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<p>The double-stranded RNA analog, poly(I:C), extracellularly activates both the endosomal Toll-like receptor (TLR) 3 and the cytoplasmic RNA helicase, melanoma differentiation-associated gene 5, leading to the production of type I interferons (IFNs) and inflammatory cytokines. The mechanism by which extracellular poly(I:C) is delivered to TLR3-positive organelles and the cytoplasm remains to be elucidated. Here, we show that the cytoplasmic lipid raft protein, Raftlin, is essential for poly(I:C) cellular uptake in human myeloid dendritic cells and epithelial cells. When Raftlin was silenced, poly(I:C) failed to enter cells and induction of IFN-β production was inhibited. In addition, cellular uptake of B-type oligodeoxynucleotide that shares its uptake receptor with poly(I:C) was suppressed in Raftlin knockdown cells. Upon poly(I:C) stimulation, Raftlin was translocated from the cytoplasm to the plasma membrane where it colocalized with poly(I:C), and thereafter moved to TLR3-positive endosomes. Thus, Raftlin cooperates with the uptake receptor to mediate cell entry of poly(I:C), which is critical for activation of TLR3. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.</p>

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Sprouty2 controls proliferation of palate mesenchymal cells via fibroblast growth factor signaling

Matsumura Kaori, Taketomi Takaharu, Yoshizaki Keigo, Arai Shinsaku, Sanui Terukazu, Yoshiga Daigo, Yoshimura Akihiko, Nakamura Seiji

Biochemical and Biophysical Research Communications 404 ( 4 ) 1076 - 1082 2011.01

ISSN  0006-291X

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<p>Cleft palate is one of the most common craniofacial deformities. The fibroblast growth factor (FGF) plays a central role in reciprocal interactions between adjacent tissues during palatal development, and the FGF signaling pathway has been shown to be inhibited by members of the Sprouty protein family. In this study, we report the incidence of cleft palate, possibly caused by failure of palatal shelf elevation, in Sprouty2-deficient (KO) mice. Sprouty2-deficient palates fused completely in palatal organ culture. However, palate mesenchymal cell proliferation estimated by Ki-67 staining was increased in Sprouty2 KO mice compared with WT mice. Sprouty2-null palates expressed higher levels of FGF target genes, such as Msx1, Etv5, and Ptx1 than WT controls. Furthermore, proliferation and the extracellular signal-regulated kinase (Erk) activation in response to FGF was enhanced in palate mesenchymal cells transfected with Sprouty2 small interfering RNA. These results suggest that Sprouty2 regulates palate mesenchymal cell proliferation via FGF signaling and is involved in palatal shelf elevation. © 2010 Elsevier Inc.</p>

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Sprouty2 controls proliferation of palate mesenchymal cells via fibroblast growth factor signaling

Matsumura Kaori, Taketomi Takaharu, Yoshizaki Keigo, Arai Shinsaku, Sanui Terukazu, Yoshiga Daigo, Yoshimura Akihiko, Nakamura Seiji

Biochemical and Biophysical Research Communications 404 ( 4 ) 1076 - 1082 2011.01

ISSN  0006-291X

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<p>Cleft palate is one of the most common craniofacial deformities. The fibroblast growth factor (FGF) plays a central role in reciprocal interactions between adjacent tissues during palatal development, and the FGF signaling pathway has been shown to be inhibited by members of the Sprouty protein family. In this study, we report the incidence of cleft palate, possibly caused by failure of palatal shelf elevation, in Sprouty2-deficient (KO) mice. Sprouty2-deficient palates fused completely in palatal organ culture. However, palate mesenchymal cell proliferation estimated by Ki-67 staining was increased in Sprouty2 KO mice compared with WT mice. Sprouty2-null palates expressed higher levels of FGF target genes, such as Msx1, Etv5, and Ptx1 than WT controls. Furthermore, proliferation and the extracellular signal-regulated kinase (Erk) activation in response to FGF was enhanced in palate mesenchymal cells transfected with Sprouty2 small interfering RNA. These results suggest that Sprouty2 regulates palate mesenchymal cell proliferation via FGF signaling and is involved in palatal shelf elevation. © 2010 Elsevier Inc.</p>

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Loss of Sprouty2 partially rescues renal hypoplasia and stomach hypoganglionosis but not intestinal aganglionosis in Ret Y1062F mutant mice

Miyamoto Rieko, Jijiwa Mayumi, Asai Masato, Kawai Kumi, Ishida-Takagishi Maki, Mii Shinji, Asai Naoya, Enomoto Atsushi, Murakumo Yoshiki, Yoshimura Akihiko, Takahashi Masahide

Developmental Biology 349 ( 2 ) 160 - 168 2011.01

ISSN  0012-1606

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<p>The glial cell line-derived neurotrophic factor (GDNF)/RET tyrosine kinase signaling pathway plays crucial roles in the development of the enteric nervous system (ENS) and the kidney. Tyrosine 1062 (Y1062) in RET is an autophosphorylation residue that is responsible for the activation of the PI3K/AKT and RAS/MAPK signaling pathways. Mice lacking signaling via Ret Y1062 show renal hypoplasia and hypoganglionosis of the ENS although the phenotype is milder than the Gdnf- or Ret-deficient mice. Sprouty2 (Spry2) was found to be an antagonist for fibroblast growth factor receptor (FGFR) and acts as an inhibitory regulator of ERK activation. Spry2-deficient mice exhibit hearing loss and enteric nerve hyperplasia. In the present study, we generated Spry2-deficient and Ret Y1062F knock-in (tyrosine 1062 is replaced with phenylalanine) double mutant mice to see if abnormalities of the ENS and kidney, caused by loss of signaling via Ret Y1062, are rescued by a deficiency of Spry2. Double mutant mice showed significant recovery of ureteric bud branching and ENS development in the stomach. These results indicate that Spry2 regulates downstream signaling mediated by GDNF/RET signaling complex in vivo. © 2010 Elsevier Inc.</p>

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Loss of Sprouty2 partially rescues renal hypoplasia and stomach hypoganglionosis but not intestinal aganglionosis in Ret Y1062F mutant mice

Miyamoto Rieko, Jijiwa Mayumi, Asai Masato, Kawai Kumi, Ishida-Takagishi Maki, Mii Shinji, Asai Naoya, Enomoto Atsushi, Murakumo Yoshiki, Yoshimura Akihiko, Takahashi Masahide

Developmental Biology 349 ( 2 ) 160 - 168 2011.01

ISSN  0012-1606

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<p>The glial cell line-derived neurotrophic factor (GDNF)/RET tyrosine kinase signaling pathway plays crucial roles in the development of the enteric nervous system (ENS) and the kidney. Tyrosine 1062 (Y1062) in RET is an autophosphorylation residue that is responsible for the activation of the PI3K/AKT and RAS/MAPK signaling pathways. Mice lacking signaling via Ret Y1062 show renal hypoplasia and hypoganglionosis of the ENS although the phenotype is milder than the Gdnf- or Ret-deficient mice. Sprouty2 (Spry2) was found to be an antagonist for fibroblast growth factor receptor (FGFR) and acts as an inhibitory regulator of ERK activation. Spry2-deficient mice exhibit hearing loss and enteric nerve hyperplasia. In the present study, we generated Spry2-deficient and Ret Y1062F knock-in (tyrosine 1062 is replaced with phenylalanine) double mutant mice to see if abnormalities of the ENS and kidney, caused by loss of signaling via Ret Y1062, are rescued by a deficiency of Spry2. Double mutant mice showed significant recovery of ureteric bud branching and ENS development in the stomach. These results indicate that Spry2 regulates downstream signaling mediated by GDNF/RET signaling complex in vivo. © 2010 Elsevier Inc.</p>

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Effects of a Janus kinase inhibitor, pyridone 6, on airway responses in a murine model of asthma

Matsunaga Yuko, Inoue Hiromasa, Fukuyama Satoru, Yoshida Hideyuki, Moriwaki Atsushi, Matsumoto Takafumi, Matsumoto Koichiro, Asai Yukari, Kubo Masato, Yoshimura Akihiko, Nakanishi Yoichi

Biochemical and Biophysical Research Communications 404 ( 1 ) 261 - 267 2011.01

ISSN  0006-291X

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<p>Th2 cytokines and their downstream Janus kinase (JAK)-signal transducer and activation of transcription (STAT) pathways play a critical role in allergic asthma. We studied the effects of a pan-JAK inhibitor, pyridone 6 (P6), on asthmatic responses in a mouse model and investigated the mechanism for its biological effects. Mice were sensitized and challenged by ovalbumin (OVA). P6 treatment during the challenge phase suppressed eosinophilia in bronchoalveolar lavage (BAL) fluids but did not affect airway hyperresponsiveness (AHR). To improve the efficacy of the JAK inhibitor, P6 was encapsulated in polylactic- coglycolic acid nanoparticles (P6-PLGA). P6-PLGA treatment just before OVA challenge suppressed both airway eosinophilia and AHR. Although the IL-13 levels in BAL fluids and the OVA-specific IgE levels in serum after the challenge phase treatment with P6-PLGA were similar to those after a sham treatment, the eotaxin levels in BAL fluids and lung mCLCA3/Gob-5 expression were decreased in P6-PLGA-treated mice. Interestingly, the local IL-13 levels and serum OVA-specific IgE were decreased, while IL-17-producing T cells were increased by P6-PLGA treatment during the sensitization plus challenge phases. In vitro, P6 strongly suppressed the differentiation of Th2 from naive CD4 T cells, but it partly enhanced Th17 differentiation. P6 potently suppressed IL-13-mediated STAT6 activation and mCLCA3/Gob-5 expression in mouse tracheal epithelial cells. These findings suggest that the JAK inhibitor P6 suppresses asthmatic responses by inhibiting Th2 inflammation and that application of PLGA nanoparticles improves the therapeutic potency of P6. © 2010 Elsevier Inc.</p>

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Effects of a Janus kinase inhibitor, pyridone 6, on airway responses in a murine model of asthma

Matsunaga Yuko, Inoue Hiromasa, Fukuyama Satoru, Yoshida Hideyuki, Moriwaki Atsushi, Matsumoto Takafumi, Matsumoto Koichiro, Asai Yukari, Kubo Masato, Yoshimura Akihiko, Nakanishi Yoichi

Biochemical and Biophysical Research Communications 404 ( 1 ) 261 - 267 2011.01

ISSN  0006-291X

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<p>Th2 cytokines and their downstream Janus kinase (JAK)-signal transducer and activation of transcription (STAT) pathways play a critical role in allergic asthma. We studied the effects of a pan-JAK inhibitor, pyridone 6 (P6), on asthmatic responses in a mouse model and investigated the mechanism for its biological effects. Mice were sensitized and challenged by ovalbumin (OVA). P6 treatment during the challenge phase suppressed eosinophilia in bronchoalveolar lavage (BAL) fluids but did not affect airway hyperresponsiveness (AHR). To improve the efficacy of the JAK inhibitor, P6 was encapsulated in polylactic- coglycolic acid nanoparticles (P6-PLGA). P6-PLGA treatment just before OVA challenge suppressed both airway eosinophilia and AHR. Although the IL-13 levels in BAL fluids and the OVA-specific IgE levels in serum after the challenge phase treatment with P6-PLGA were similar to those after a sham treatment, the eotaxin levels in BAL fluids and lung mCLCA3/Gob-5 expression were decreased in P6-PLGA-treated mice. Interestingly, the local IL-13 levels and serum OVA-specific IgE were decreased, while IL-17-producing T cells were increased by P6-PLGA treatment during the sensitization plus challenge phases. In vitro, P6 strongly suppressed the differentiation of Th2 from naive CD4 T cells, but it partly enhanced Th17 differentiation. P6 potently suppressed IL-13-mediated STAT6 activation and mCLCA3/Gob-5 expression in mouse tracheal epithelial cells. These findings suggest that the JAK inhibitor P6 suppresses asthmatic responses by inhibiting Th2 inflammation and that application of PLGA nanoparticles improves the therapeutic potency of P6. © 2010 Elsevier Inc.</p>

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Smad2 and Smad3 are redundantly essential for the TGF-β-mediated regulation of regulatory T plasticity and Th1 development (Journal of Immunology (2010) 185, (842-855))

Takimoto T., Wakabayashi Y., Sekiya T., Inoue N., Morita R., Ichiyama K., Takahashi R., Asakawa M., Muto G., Mori T., Hasegawa E., Shizuya S., Hara T., Nomura M., Yoshimura A.

Journal of Immunology 186 ( 1 ) 632 2011.01

ISSN  0022-1767

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Smad2 and Smad3 are redundantly essential for the TGF-β-mediated regulation of regulatory T plasticity and Th1 development (Journal of Immunology (2010) 185, (842-855))

Takimoto T., Wakabayashi Y., Sekiya T., Inoue N., Morita R., Ichiyama K., Takahashi R., Asakawa M., Muto G., Mori T., Hasegawa E., Shizuya S., Hara T., Nomura M., Yoshimura A.

Journal of Immunology 186 ( 1 ) 632 2011.01

ISSN  0022-1767

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Legius syndrome in fourteen families

Denayer Ellen, Chmara Magdalena, Brems Hilde, Kievit Anneke Maat, Van Bever Yolande, Van Den Ouweland Ans M W, Van Minkelen Rick, De Goede-Bolder Arja, Oostenbrink Rianne, Lakeman Phillis, Beert Eline, Ishizaki Takuma, Mori Tomoaki, Keymolen Kathelijn, Van Den Ende Jenneke, Mangold Elisabeth, Peltonen Sirkku, Brice Glen, Rankin Julia, Van Spaendonck-Zwarts Karin Y., Yoshimura Akihiko, Legius Eric

Human Mutation 32 ( 1 )  2011.01

ISSN  1059-7794

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<p>Legius syndrome presents as an autosomal dominant condition characterized by café-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius syndrome. © 2010 Wiley-Liss, Inc.</p>

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[Suppression of leptin and insulin signaling by SOCS3].

Yoshimura Akihiko

Nihon rinsho. Japanese journal of clinical medicine 69 Suppl 1   782 - 789 2011.01

ISSN  0047-1852