論文 - 吉村　昭彦

A gp130-Src-YAP module links inflammation to epithelial regeneration

Taniguchi Koji, Wu Li Wha, Grivennikov Sergei I., De Jong Petrus R., Lian Ian, Yu Fa Xing, Wang Kepeng, Ho Samuel B., Boland Brigid S., Chang John T., Sandborn William J., Hardiman Gary, Raz Eyal, Maehara Yoshihiko, Yoshimura Akihiko, Zucman-Rossi Jessica, Guan Kun Liang, Karin Michael

Nature 519 （ 7541 ） 57 - 62 2015年03月

ISSN  0028-0836

　概要を見る

<p>Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.</p>

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Anti-IL-1^-/-3 p40 antibody attenuates experimental chronic graft-versus-host disease via suppression of IFN-γ/IL-17-producing cells

Okamoto Sachiyo, Fujiwara Hideaki, Nishimori Hisakazu, Matsuoka Ken Ichi, Fujii Nobuharu, Kondo Eisei, Tanaka Takehiro, Yoshimura Akihiko, Tanimoto Mitsune, Maeda Yoshinobu

Journal of Immunology 194 （ 3 ） 1357 - 1363 2015年02月

ISSN  0022-1767

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<p>Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation. Recently, in addition to Th2 cells, Th1 and Th17 cells have been shown to contribute to chronic GVHD progression. IL-12 induces Th1 cells and IL-23 plays a role in stabilizing and/or amplifying Th17 cells, as well as in inducing IFN-γ/IL-17 double-producing cells. Because mAb targeting the p40 subunit common to both IL-12 and IL-23 can inhibit both IL-12R and IL-23R-mediated signaling, we investigated the effects of anti-p40 mAb on a well-defined chronic GVHD mice model. Treatment of anti-p40 mAb in allogeneic recipients significantly reduced the severity of clinical and pathological chronic GVHD. Intracellular staining revealed that IFN-γ single-positive (IL-17^-) and IFN-γ/IL-17 double-positive cells were suppressed in anti-p40 mAb-treated allogeneic recipients compared with control recipients. The cytokine levels of IFN-γ and IL-17 were also decreased in serum from anti-p40 mAb-treated allogeneic recipients. T-bet expression of donor IL-17⁺ CD4⁺ T cells was reduced significantly in anti-p40 mAb-treated recipients, and this reduction in T-bet expression was associated with IL-22 production by donor T cells. These results suggested that anti-p40 mAb attenuated chronic GVHD via suppression of IFN-γ/IL-17-producing cells, and that targeting the IL-12/IL-23 pathway may represent a promising therapeutic strategy for preventing and treating chronic GVHD.</p>

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Anti-IL-1^-/-3 p40 antibody attenuates experimental chronic graft-versus-host disease via suppression of IFN-γ/IL-17-producing cells

Okamoto Sachiyo, Fujiwara Hideaki, Nishimori Hisakazu, Matsuoka Ken Ichi, Fujii Nobuharu, Kondo Eisei, Tanaka Takehiro, Yoshimura Akihiko, Tanimoto Mitsune, Maeda Yoshinobu

Journal of Immunology 194 （ 3 ） 1357 - 1363 2015年02月

ISSN  0022-1767

　概要を見る

<p>Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation. Recently, in addition to Th2 cells, Th1 and Th17 cells have been shown to contribute to chronic GVHD progression. IL-12 induces Th1 cells and IL-23 plays a role in stabilizing and/or amplifying Th17 cells, as well as in inducing IFN-γ/IL-17 double-producing cells. Because mAb targeting the p40 subunit common to both IL-12 and IL-23 can inhibit both IL-12R and IL-23R-mediated signaling, we investigated the effects of anti-p40 mAb on a well-defined chronic GVHD mice model. Treatment of anti-p40 mAb in allogeneic recipients significantly reduced the severity of clinical and pathological chronic GVHD. Intracellular staining revealed that IFN-γ single-positive (IL-17^-) and IFN-γ/IL-17 double-positive cells were suppressed in anti-p40 mAb-treated allogeneic recipients compared with control recipients. The cytokine levels of IFN-γ and IL-17 were also decreased in serum from anti-p40 mAb-treated allogeneic recipients. T-bet expression of donor IL-17⁺ CD4⁺ T cells was reduced significantly in anti-p40 mAb-treated recipients, and this reduction in T-bet expression was associated with IL-22 production by donor T cells. These results suggested that anti-p40 mAb attenuated chronic GVHD via suppression of IFN-γ/IL-17-producing cells, and that targeting the IL-12/IL-23 pathway may represent a promising therapeutic strategy for preventing and treating chronic GVHD.</p>

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ETS transcription factor ETV2 directly converts human fibroblasts into functional endothelial cells

Morita Rimpei, Suzuki Mayu, Kasahara Hidenori, Shimizu Nana, Shichita Takashi, Sekiya Takashi, Kimura Akihiro, Sasaki Ken Ichiro, Yasukawa Hideo, Yoshimura Akihiko

Proceedings of the National Academy of Sciences of the United States of America 112 （ 1 ） 160 - 165 2015年01月

ISSN  0027-8424

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<p>Transplantation of endothelial cells (ECs) is a promising therapeutic approach for ischemic disorders. In addition, the generation of ECs has become increasingly important for providing vascular plexus to regenerated organs, such as the liver. Although many attempts have been made to generate ECs from pluripotent stem cells and nonvascular cells, the minimum number of transcription factors that specialize in directly inducing vascular ECs remains undefined. Here, by screening 18 transcription factors that are important for both endothelial and hematopoietic development, we demonstrate that ets variant 2 (ETV2) alone directly converts primary human adult skin fibroblasts into functional vascular endothelial cells (ETVECs). In coordination with endogenous FOXC2 in fibroblasts, transduced ETV2 elicits expression of multiple key endothelial development factors, including FLI1, ERG, and TAL1, and induces expression of endothelial functional molecules, including EGFL7 and von Willebrand factor. Consequently, ETVECs exhibits EC characteristics in vitro and forms mature functional vasculature in Matrigel plugs transplanted in NOD SCID mice. Furthermore, ETVECs significantly improve blood flow recovery in a hind limb ischemic model using BALB/c-nu mice. Our study indicates that the creation of ETVECs provides further understanding of human EC development induced by ETV2.</p>

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ETS transcription factor ETV2 directly converts human fibroblasts into functional endothelial cells

Morita Rimpei, Suzuki Mayu, Kasahara Hidenori, Shimizu Nana, Shichita Takashi, Sekiya Takashi, Kimura Akihiro, Sasaki Ken Ichiro, Yasukawa Hideo, Yoshimura Akihiko

Proceedings of the National Academy of Sciences of the United States of America 112 （ 1 ） 160 - 165 2015年01月

ISSN  0027-8424

　概要を見る

<p>Transplantation of endothelial cells (ECs) is a promising therapeutic approach for ischemic disorders. In addition, the generation of ECs has become increasingly important for providing vascular plexus to regenerated organs, such as the liver. Although many attempts have been made to generate ECs from pluripotent stem cells and nonvascular cells, the minimum number of transcription factors that specialize in directly inducing vascular ECs remains undefined. Here, by screening 18 transcription factors that are important for both endothelial and hematopoietic development, we demonstrate that ets variant 2 (ETV2) alone directly converts primary human adult skin fibroblasts into functional vascular endothelial cells (ETVECs). In coordination with endogenous FOXC2 in fibroblasts, transduced ETV2 elicits expression of multiple key endothelial development factors, including FLI1, ERG, and TAL1, and induces expression of endothelial functional molecules, including EGFL7 and von Willebrand factor. Consequently, ETVECs exhibits EC characteristics in vitro and forms mature functional vasculature in Matrigel plugs transplanted in NOD SCID mice. Furthermore, ETVECs significantly improve blood flow recovery in a hind limb ischemic model using BALB/c-nu mice. Our study indicates that the creation of ETVECs provides further understanding of human EC development induced by ETV2.</p>

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Distinct effects of endogenous interleukin-23 on eosinophilic airway inflammation in response to different antigens

Ogawa Rika, Suzuki Yusuke, Kagawa Shizuko, Masaki Katsunori, Fukunaga Koichi, Yoshimura Akihiko, Fujishima Seitaro, Terashima Takeshi, Betsuyaku Tomoko, Asano Koichiro

Allergology International 2015年01月

ISSN  1323-8930

　概要を見る

<p>Background: The role of interleukin (IL)-23 in asthma pathophysiology is still controversial. We examined its role in allergic airway inflammation in response to two distinct antigens using IL-23-deficient mice. Methods: Allergic airway inflammation was evaluated in wild-type and IL-23p19 &lt;sup&gt;-/-&lt;/sup&gt; mice. Mice were sensitized to ovalbumin (OVA) or house dust mite (HDM) by intraperitoneal injection of antigen and their airways were then exposed to the same antigen. Levels of antigen-specific immunoglobulins in serum as well as cytokines in bronchoalveolar or peritoneal lavage fluid and lung tissue were determined by enzyme-linked immunosorbent assay and/or quantitative polymerase chain reaction. Results: Deficiency of IL-23p19 decreased eosinophils and Th2 cytokines in bronchoalveolar lavage fluid (BALF) of OVA-treated mice, while it increased BALF eosinophils of HDM-treated mice. Peritoneal injection of OVA with alum, but not of HDM, induced local synthesis of IL-6, IL-10, and IL-23. Systemic production of antigen-specific IgG&lt;inf&gt;1&lt;/inf&gt; was partially dependent on IL-23. In contrast, airway exposure to HDM, but not to OVA, induced IL-23p19 mRNA expression in the lungs. In IL-23p19-deficient mice, HDM-exposed lungs did not exhibit the induction of IL-17A, which negatively regulates eosinophilic inflammation. Conclusions: Different antigens induced IL-23 at different part of the body in our similar asthma models. Endogenous IL-23 production at the site of antigen sensitization facilitates type-2 immune responses, whereas IL-23 production and subsequent IL-17A synthesis in the airways suppresses allergic inflammation.</p>

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Distinct effects of endogenous interleukin-23 on eosinophilic airway inflammation in response to different antigens

Ogawa Rika, Suzuki Yusuke, Kagawa Shizuko, Masaki Katsunori, Fukunaga Koichi, Yoshimura Akihiko, Fujishima Seitaro, Terashima Takeshi, Betsuyaku Tomoko, Asano Koichiro

Allergology International 2015年01月

ISSN  1323-8930

　概要を見る

<p>Background: The role of interleukin (IL)-23 in asthma pathophysiology is still controversial. We examined its role in allergic airway inflammation in response to two distinct antigens using IL-23-deficient mice. Methods: Allergic airway inflammation was evaluated in wild-type and IL-23p19 &lt;sup&gt;-/-&lt;/sup&gt; mice. Mice were sensitized to ovalbumin (OVA) or house dust mite (HDM) by intraperitoneal injection of antigen and their airways were then exposed to the same antigen. Levels of antigen-specific immunoglobulins in serum as well as cytokines in bronchoalveolar or peritoneal lavage fluid and lung tissue were determined by enzyme-linked immunosorbent assay and/or quantitative polymerase chain reaction. Results: Deficiency of IL-23p19 decreased eosinophils and Th2 cytokines in bronchoalveolar lavage fluid (BALF) of OVA-treated mice, while it increased BALF eosinophils of HDM-treated mice. Peritoneal injection of OVA with alum, but not of HDM, induced local synthesis of IL-6, IL-10, and IL-23. Systemic production of antigen-specific IgG&lt;inf&gt;1&lt;/inf&gt; was partially dependent on IL-23. In contrast, airway exposure to HDM, but not to OVA, induced IL-23p19 mRNA expression in the lungs. In IL-23p19-deficient mice, HDM-exposed lungs did not exhibit the induction of IL-17A, which negatively regulates eosinophilic inflammation. Conclusions: Different antigens induced IL-23 at different part of the body in our similar asthma models. Endogenous IL-23 production at the site of antigen sensitization facilitates type-2 immune responses, whereas IL-23 production and subsequent IL-17A synthesis in the airways suppresses allergic inflammation.</p>

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Suppressor of cytokine signaling 3 is an inducible host factor that regulates virus egress during Ebola virus infection

Okumura Atsushi, Rasmussen Angela L., Halfmann Peter, Feldmann Friederike, Yoshimura Akihiko, Feldmann Heinz, Kawaoka Yoshihiro, Harty Ronald N., Katze Michael G.

Journal of Virology 89 （ 20 ） 10399 - 10406 2015年

ISSN  0022-538X

　概要を見る

<p>Ebola virus (EBOV) initially targets monocytes and macrophages, which can lead to the release of proinflammatory cytokines and chemokines. These inflammatory cytokines are thought to contribute to the development of circulatory shock seen in fatal EBOV infections. The VP40 matrix protein is a key viral structural protein that is critical for virion egress. Physical and functional interactions between VP40 and host proteins such as Tsg101 and Nedd4 facilitate efficient release of VP40-driven viruslike particles (VLPs) and infectious virus. Here, we show that host suppressor of cytokine signaling 3 (SOCS3) can also bind to EBOV VP40, leading to enhanced ubiquitinylation and egress of VP40. Indeed, titers of infectious EBOV derived from SOCS3 knockout mouse embryonic fibroblasts (MEFs) were significantly reduced compared to those from wild-type (WT) MEFs at 24 and 48 h postinfection. Importantly, this reduced virus yield could be rescued back to WT levels by exogenously expressing SOCS3. Lastly, we show that SOCS3 expression is induced by EBOV glycoprotein (GP) expression and that VLPs containing EBOV VP40 and GP induced production of proinflammatory cytokines, which induced SOCS3 for negative-feedback regulation. These data indicate that host innate immune protein SOCS3 may play an important role in budding and pathogenesis of EBOV.</p>

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Resolution of elevated circulating regulatory T cells by corticosteroids in patients with IgG4-related dacryoadenitis and sialoadenitis

Akiyama Mitsuhiro, Suzuki Katsuya, Kassai Yoshiaki, Miyazaki Takahiro, Morita Rimpei, Yoshimura Akihiko, Takeuchi Tsutomu

International Journal of Rheumatic Diseases 2015年

ISSN  1756-1841

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Resolution of elevated circulating regulatory T cells by corticosteroids in patients with IgG4-related dacryoadenitis and sialoadenitis

Akiyama Mitsuhiro, Suzuki Katsuya, Kassai Yoshiaki, Miyazaki Takahiro, Morita Rimpei, Yoshimura Akihiko, Takeuchi Tsutomu

International Journal of Rheumatic Diseases 2015年

ISSN  1756-1841

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The lysosome rupture-activated TAK1-JNK pathway regulates NLRP3 inflammasome activation

Okada Masahiro, Matsuzawa Atsushi, Yoshimura Akihiko, Ichijo Hidenori

Journal of Biological Chemistry 289 （ 47 ） 32926 - 32936 2014年11月

ISSN  0021-9258

　概要を見る

<p>Results: Inhibition of CaMKII, TAK1, or JNK specifically suppressed lysosome rupture-induced NLRP3 inflammasome activation.</p><p>Background: The mechanisms underlying lysosome rupture-mediated inflammasome activation are not understood.</p><p>Conclusion: Activation of the Ca²⁺-CaMKII-TAK1-JNK pathway in lysosome rupture is necessary for complete activation of the NLRP3 inflammasome.</p><p>Significance: Our results suggest novel roles for the Ca²⁺-CaMKII-TAK1-JNK pathway in the regulation of the inflammasome and propose potential therapeutic targets for inflammatory diseases.</p>

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The lysosome rupture-activated TAK1-JNK pathway regulates NLRP3 inflammasome activation

Okada Masahiro, Matsuzawa Atsushi, Yoshimura Akihiko, Ichijo Hidenori

Journal of Biological Chemistry 289 （ 47 ） 32926 - 32936 2014年11月

ISSN  0021-9258

　概要を見る

<p>Results: Inhibition of CaMKII, TAK1, or JNK specifically suppressed lysosome rupture-induced NLRP3 inflammasome activation.</p><p>Background: The mechanisms underlying lysosome rupture-mediated inflammasome activation are not understood.</p><p>Conclusion: Activation of the Ca²⁺-CaMKII-TAK1-JNK pathway in lysosome rupture is necessary for complete activation of the NLRP3 inflammasome.</p><p>Significance: Our results suggest novel roles for the Ca²⁺-CaMKII-TAK1-JNK pathway in the regulation of the inflammasome and propose potential therapeutic targets for inflammatory diseases.</p>

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Post-ischemic inflammation regulates neural damage and protection

Shichita Takashi, Ito Minako, Yoshimura Akihiko

Frontiers in Cellular Neuroscience 8 （ OCT ）  2014年10月

ISSN  1662-5102

　概要を見る

<p>Post-ischemic inflammation is important in ischemic stroke pathology. However, details of the inflammation process, its resolution after stroke and its effect on pathology and neural damage have not been clarified. Brain swelling, which is often fatal in ischemic stroke patients, occurs at an early stage of stroke due to endothelial cell injury and severe inflammation by infiltrated mononuclear cells including macrophages, neutrophils, and lymphocytes. At early stage of inflammation, macrophages are activated by molecules released from necrotic cells [danger-associated molecular patterns (DAMPs)], and inflammatory cytokines and mediators that increase ischemic brain damage by disruption of the blood–brain barrier are released. After post-ischemic inflammation, macrophages function as scavengers of necrotic cell and brain tissue debris. Such macrophages are also involved in tissue repair and neural cell regeneration by producing tropic factors. The mechanisms of inflammation resolution and conversion of inflammation to neuroprotection are largely unknown. In this review, we summarize information accumulated recently about DAMP-induced inflammation and the neuroprotective effects of inflammatory cells, and discuss next generation strategies to treat ischemic stroke.</p>

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Post-ischemic inflammation regulates neural damage and protection

Shichita Takashi, Ito Minako, Yoshimura Akihiko

Frontiers in Cellular Neuroscience 8 （ OCT ）  2014年10月

ISSN  1662-5102

　概要を見る

<p>Post-ischemic inflammation is important in ischemic stroke pathology. However, details of the inflammation process, its resolution after stroke and its effect on pathology and neural damage have not been clarified. Brain swelling, which is often fatal in ischemic stroke patients, occurs at an early stage of stroke due to endothelial cell injury and severe inflammation by infiltrated mononuclear cells including macrophages, neutrophils, and lymphocytes. At early stage of inflammation, macrophages are activated by molecules released from necrotic cells [danger-associated molecular patterns (DAMPs)], and inflammatory cytokines and mediators that increase ischemic brain damage by disruption of the blood–brain barrier are released. After post-ischemic inflammation, macrophages function as scavengers of necrotic cell and brain tissue debris. Such macrophages are also involved in tissue repair and neural cell regeneration by producing tropic factors. The mechanisms of inflammation resolution and conversion of inflammation to neuroprotection are largely unknown. In this review, we summarize information accumulated recently about DAMP-induced inflammation and the neuroprotective effects of inflammatory cells, and discuss next generation strategies to treat ischemic stroke.</p>

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Loss of Sprouty4 in T cells ameliorates experimental autoimmune encephalomyelitis in mice by negatively regulating IL-1β receptor expression

Fukaya Tomohiro, Someya Kazue, Hibino Sana, Okada Masahiro, Yamane Humitsugu, Taniguchi Koji, Yoshimura Akihiko

Biochemical and Biophysical Research Communications 447 （ 3 ） 471 - 478 2014年05月

ISSN  0006-291X

　概要を見る

<p>Th17 cells, which have been implicated in autoimmune diseases, require IL-6 and TGF-β for early differentiation. To gain pathogenicity, however, Th17 cells require IL-1β and IL-23. The underlying mechanism by which these confer pathogenicity is not well understood. Here we show that Sprouty4, an inhibitor of the PLCγ-ERK pathway, critically regulates inflammatory Th17 (iTh17) cell differentiation. Sprouty4-deficient mice, as well as mice adoptively transferred with Sprouty4-deficient T cells, were resistant to experimental autoimmune encephalitis (EAE) and showed decreased Th17 cell generation in vivo. In vitro, Sprouty4 deficiency did not severely affect TGF-β/IL-6-induced Th17 cell generation but strongly impaired Th17 differentiation induced by IL-1/IL-6/IL-23. Analysis of Th17-related gene expression revealed that Sprouty4-deficient Th17 cells expressed lower levels of IL-1R1 and IL-23R, while RORγt levels were similar. Consistently, overexpression of Sprouty4 or pharmacological inhibition of ERK upregulated IL-1R1 expression in primary T cells. Thus, Sprouty4 and ERK play a critical role in developing iTh17 cells in Th17 cell-driven autoimmune diseases. © 2014 Elsevier Inc.</p>

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Loss of Sprouty4 in T cells ameliorates experimental autoimmune encephalomyelitis in mice by negatively regulating IL-1β receptor expression

Fukaya Tomohiro, Someya Kazue, Hibino Sana, Okada Masahiro, Yamane Humitsugu, Taniguchi Koji, Yoshimura Akihiko

Biochemical and Biophysical Research Communications 447 （ 3 ） 471 - 478 2014年05月

ISSN  0006-291X

　概要を見る

<p>Th17 cells, which have been implicated in autoimmune diseases, require IL-6 and TGF-β for early differentiation. To gain pathogenicity, however, Th17 cells require IL-1β and IL-23. The underlying mechanism by which these confer pathogenicity is not well understood. Here we show that Sprouty4, an inhibitor of the PLCγ-ERK pathway, critically regulates inflammatory Th17 (iTh17) cell differentiation. Sprouty4-deficient mice, as well as mice adoptively transferred with Sprouty4-deficient T cells, were resistant to experimental autoimmune encephalitis (EAE) and showed decreased Th17 cell generation in vivo. In vitro, Sprouty4 deficiency did not severely affect TGF-β/IL-6-induced Th17 cell generation but strongly impaired Th17 differentiation induced by IL-1/IL-6/IL-23. Analysis of Th17-related gene expression revealed that Sprouty4-deficient Th17 cells expressed lower levels of IL-1R1 and IL-23R, while RORγt levels were similar. Consistently, overexpression of Sprouty4 or pharmacological inhibition of ERK upregulated IL-1R1 expression in primary T cells. Thus, Sprouty4 and ERK play a critical role in developing iTh17 cells in Th17 cell-driven autoimmune diseases. © 2014 Elsevier Inc.</p>

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Signal-transducing adaptor protein-2 controls the IgE-Mediated, mast cell-mediated anaphylactic responses

Sekine Yuichi, Nishida Keigo, Yamasaki Satoru, Muromoto Ryuta, Kon Shigeyuki, Kashiwakura Jun Ichi, Saitoh Kodai, Togi Sumihito, Yoshimura Akihiko, Oritani Kenji, Matsuda Tadashi

Journal of Immunology 192 （ 8 ） 3488 - 3495 2014年04月

ISSN  0022-1767

　概要を見る

<p>Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that regulates immune and inflammatory responses through interactions with a variety of signaling and transcriptional molecules. In the current study, we clarified the physiological role of STAP-2 in mast cell function, a key mediator of IgE-associated allergic responses. STAP-2 is constitutively expressed in mast cells. STAP-2 deficiency in mast cells greatly enhances FcRI-mediated signals, resulting in the increased tyrosine phosphorylation of the phospholipase C-g isoform, calcium mobilization, and degranulation. Of importance, STAP-2-deficient mice challenged with DNP-BSA after passive sensitization with anti-DNP IgE show more severe rectal temperature decrease than do wild-type mice. STAP-2-deficient mice also show increased vascular permeability and more severe cutaneous anaphylaxis after DNP-BSA injection. These regulatory functions performed by STAP-2 indicate that there is an interaction between STAP-2 and FcRI. In addition, our previous data indicate that STAP-2 binds to the phospholipase C-g isoform and IkB kinase-b. Therefore, our data described in this article strongly suggest that manipulation of STAP-2 expression in mast cells may control the pathogenesis of allergic diseases and have the potential for treating patients with allergy. Copyright © 2014 by The American Association of Immunologists, Inc.</p>

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Signal-transducing adaptor protein-2 controls the IgE-Mediated, mast cell-mediated anaphylactic responses

Sekine Yuichi, Nishida Keigo, Yamasaki Satoru, Muromoto Ryuta, Kon Shigeyuki, Kashiwakura Jun Ichi, Saitoh Kodai, Togi Sumihito, Yoshimura Akihiko, Oritani Kenji, Matsuda Tadashi

Journal of Immunology 192 （ 8 ） 3488 - 3495 2014年04月

ISSN  0022-1767

　概要を見る

<p>Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that regulates immune and inflammatory responses through interactions with a variety of signaling and transcriptional molecules. In the current study, we clarified the physiological role of STAP-2 in mast cell function, a key mediator of IgE-associated allergic responses. STAP-2 is constitutively expressed in mast cells. STAP-2 deficiency in mast cells greatly enhances FcRI-mediated signals, resulting in the increased tyrosine phosphorylation of the phospholipase C-g isoform, calcium mobilization, and degranulation. Of importance, STAP-2-deficient mice challenged with DNP-BSA after passive sensitization with anti-DNP IgE show more severe rectal temperature decrease than do wild-type mice. STAP-2-deficient mice also show increased vascular permeability and more severe cutaneous anaphylaxis after DNP-BSA injection. These regulatory functions performed by STAP-2 indicate that there is an interaction between STAP-2 and FcRI. In addition, our previous data indicate that STAP-2 binds to the phospholipase C-g isoform and IkB kinase-b. Therefore, our data described in this article strongly suggest that manipulation of STAP-2 expression in mast cells may control the pathogenesis of allergic diseases and have the potential for treating patients with allergy. Copyright © 2014 by The American Association of Immunologists, Inc.</p>

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A proteomic approach for the elucidation of the specificity of ectodomain shedding

Shirakabe Kyoko, Shibagaki Yoshio, Yoshimura Akihiko, Koyasu Shigeo, Hattori Seisuke

Journal of Proteomics 98   233 - 243 2014年02月

ISSN  1874-3919

　概要を見る

<p>Ectodomain shedding (shedding) is a posttranslational modification mechanism, which liberates extracellular domains of membrane proteins through juxtamembrane processing. Because shedding alters cell characteristics in a rapid and irreversible manner, it must be strictly regulated. However, the regulatory mechanisms of shedding in response to environmental changes remain obscure. To evaluate the regulatory mechanisms of endogenous shedding, we previously developed a proteomic screening system to identify shedding targets. This system revealed a comprehensive picture of membrane proteins shed under defined conditions. In this study, we have improved the screening system to compare the shedding patterns in a mouse macrophage cell line treated with two different shedding inducers, lipopolysaccharide (LPS) and 12. O-tetradecanoylphorbol 13-acetate (TPA). We show here that LPS simultaneously activates the shedding of multiple membrane proteins. We further show that TPA specifically activates the shedding of αM/β2 integrin (Mac-1), which was not shed upon LPS-stimulation of macrophages. These results clearly demonstrate that the regulation of endogenous membrane protein shedding is both stimulus- and substrate-specific. Biological significance: The shedding targets reported to date play pivotal roles in a variety of biological phenomena, including the immunological response, cell growth, cell adhesion and cell movement. In addition, several disease-related membrane proteins are shedding targets. Thus, understanding the regulation of shedding is important for the elucidation of pathogenesis and the development of therapeutic strategies. We submit that a comprehensive characterization of endogenous shedding is indispensable for understanding the regulatory mechanisms of shedding, and thus have developed a proteomic screening system to identify shedding targets. In this study, using our screening system, we demonstrate that different extracellular stimuli activate different types of shedding, even in a single cell. Our results prove that this proteomic approach is quite effective for the elucidation of the regulatory mechanisms of shedding. © 2014 Elsevier B.V.</p>

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A proteomic approach for the elucidation of the specificity of ectodomain shedding

Shirakabe Kyoko, Shibagaki Yoshio, Yoshimura Akihiko, Koyasu Shigeo, Hattori Seisuke

Journal of Proteomics 98   233 - 243 2014年02月

ISSN  1874-3919

　概要を見る

<p>Ectodomain shedding (shedding) is a posttranslational modification mechanism, which liberates extracellular domains of membrane proteins through juxtamembrane processing. Because shedding alters cell characteristics in a rapid and irreversible manner, it must be strictly regulated. However, the regulatory mechanisms of shedding in response to environmental changes remain obscure. To evaluate the regulatory mechanisms of endogenous shedding, we previously developed a proteomic screening system to identify shedding targets. This system revealed a comprehensive picture of membrane proteins shed under defined conditions. In this study, we have improved the screening system to compare the shedding patterns in a mouse macrophage cell line treated with two different shedding inducers, lipopolysaccharide (LPS) and 12. O-tetradecanoylphorbol 13-acetate (TPA). We show here that LPS simultaneously activates the shedding of multiple membrane proteins. We further show that TPA specifically activates the shedding of αM/β2 integrin (Mac-1), which was not shed upon LPS-stimulation of macrophages. These results clearly demonstrate that the regulation of endogenous membrane protein shedding is both stimulus- and substrate-specific. Biological significance: The shedding targets reported to date play pivotal roles in a variety of biological phenomena, including the immunological response, cell growth, cell adhesion and cell movement. In addition, several disease-related membrane proteins are shedding targets. Thus, understanding the regulation of shedding is important for the elucidation of pathogenesis and the development of therapeutic strategies. We submit that a comprehensive characterization of endogenous shedding is indispensable for understanding the regulatory mechanisms of shedding, and thus have developed a proteomic screening system to identify shedding targets. In this study, using our screening system, we demonstrate that different extracellular stimuli activate different types of shedding, even in a single cell. Our results prove that this proteomic approach is quite effective for the elucidation of the regulatory mechanisms of shedding. © 2014 Elsevier B.V.</p>

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