Details of a Researcher - Yoshimura, Akihiko

Papers - Yoshimura, Akihiko

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Corrigendum to "A novel zinc finger protein, ZCCHC11, interacts with TIFA and modulates TLR signaling" [Biochem. Biophys. Res. Commun. 344 (2006) 1023-1030] (DOI

Minoda Yasumasa, Saeki Kazuko, Aki Daisuke, Takaki Hiromi, Sanada Takahito, Koga Keiko, Kobayashi Takashi, Takaesu Giichi, Yoshimura Akihiko

Biochemical and Biophysical Research Communications 353 ( 4 ) 1121 2007.02

ISSN 0006-291X

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The dual function of hepatic SOCS3 in insulin resistance in vivo

Torisu Takehiro, Sato Naoichi, Yoshiga Daigo, Kobayashi Takashi, Yoshioka Tomoko, Mori Hiroyuki, Iida Mitsuo, Yoshimura Akihiko

Genes to Cells 12 ( 2 ) 143 - 154 2007.02

ISSN 1356-9597

Inflammation associates with insulin resistance, which dysregulates nutrient homeostasis and leads to diabetes. The suppressor of cytokine signaling 3 (SOCS3), which is induced by pro-inflammatory cytokines, such as TNFα and IL-6, has been implicated in inflammation-mediated insulin resistance in the liver and adipocytes. However, no genetic evidence has been provided for the involvement of SOCS3 on insulin resistance. Here, we generated hepatocyte-specific SOCS3-deficient (L-SOCS3 cKO) mice and examined insulin sensitivity. Being consistent with a previous idea, the loss of SOCS3 in the liver apparently improved insulin sensitivity. However, unexpectedly, L-SOCS3 cKO mice exhibited obesity and systemic insulin resistance with age. Insulin signaling was rather suppressed in muscles, suggesting that deletion of the SOCS3 gene in the liver modulates insulin sensitivity in other organs. Anti-inflammatory reagent, sodium salicylate, partial improved insulin resistance of aged L-SOCS3 cKO mice, suggesting that enhanced inflammatory status is associated with the phenotype of these mice. STAT3 was hyperactivated and acute-phase proteins were elevated in L-SOCS3 cKO mice liver, which were reduced by sodium salicylate treatment. We conclude that hepatic SOCS3 is a mediator of insulin resistance in the liver; however, lack of SOCS3 in the liver promotes systemic insulin resistance by mimicking chronic inflammation. © 2007 The Authors Journal compilation © 2007 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.

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Sprouty2 and Sprouty4 are essential for embryonic morphogenesis and regulation of FGF signaling

Taniguchi Koji, Ayada Toranoshin, Ichiyama Kenji, Kohno Ri ichiro, Yonemitsu Yoshikazu, Minami Yasuhiro, Kikuchi Akira, Maehara Yoshihiko, Yoshimura Akihiko

Biochemical and Biophysical Research Communications 352 ( 4 ) 896 - 902 2007.01

ISSN 0006-291X

Sprouty genes encode cytoplasmic membrane-associated proteins that inhibit receptor tyrosine kinase signaling. Four orthologs of Drosophila Sprouty (dSpry) (Sprouty1-4) have been identified in mammals. Physiological function of Sprouty1 and Sprouty2 has been investigated using gene targeting approaches, however to date detailed examination of Sprouty4 knockout (KO) mice has not been reported. In this study, Sprouty4 KO mice were generated and characterized. Although a significant fraction of Sprouty4 KO mice died shortly after birth due to mandible defects, the remainder were viable and fertile. Growth retardation was observed for most Sprouty4-deficient mice, with nearly all Sprouty4 KO mice having polysyndactyly. ERK activation was sustained in Sprouty4 KO mouse embryonic fibroblasts (MEFs) in response to FGF, but not to EGF. Sprouty2 and Sprouty4 double KO (DKO) mice were embryonic lethal and showed severe defects in craniofacial, limb, and lung morphogenesis. These findings suggest both redundant and non-redundant functions for Sprouty2 and Sprouty4 on embryonic development and FGF signaling. © 2006 Elsevier Inc. All rights reserved.

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Role of endogenous inhibitors of cytokine signaling in allergic asthma

Inoue Hiromasa, Fukuyama Satoru, Matsumoto Koichiro, Kubo Masato, Yoshimura Akihiko

Current Medicinal Chemistry 14 ( 2 ) 181 - 189 2007.01

ISSN 0929-8673

T helper 2 cytokines, including interleukin (IL)-4, IL-5, and IL-13, play an important role in allergic immune disorders, such as bronchial asthma. These cytokines regulate diverse biological functions by binding to receptors at the cell surface to activate complex signal transduction pathways, including the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and the Ras-extracellular signal-regulated kinase (ERK) signaling pathways. The suppressor of cytokine signaling (SOCS) family proteins has been shown to regulate the JAK-STAT pathway, and the Sprouty-related EVH1-domain-containing protein (SPRED) family proteins regulate the Ras-ERK pathway. SOCS3 and SOCS5 are predominantly expressed in Th2 and Th1 cells, respectively, and they reciprocally inhibit the Th1 and Th2 differentiation processes. SOCS3 also has a role in Th3 differentiation. SPRED-1 is expressed in hematopoietic cells, including eosinophils, and negatively controls the eosinophil numbers and functions by modulating IL-5 signaling. Here, we discuss the role of SOCS and SPRED proteins in allergic asthma and explore the potential of these proteins as targets for therapeutic strategies in allergic asthma. © 2007 Bentham Science Publishers Ltd.

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Positive and negative roles of IL-6, STAT3, and SOCS3 in inflammatory arthritis

Kinjyo Ichiko, Ohishi Masanobu, Shouda Takanori, Kobayashi Takashi, Yoshimura Akihiko

113 - 124 2007

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Loss of SOCS3 gene expression converts STAT3 function from anti-apoptotic to pro-apoptotic

Lu Yang, Fukuyama Satoru, Yoshida Ryoko, Kobayashi Takashi, Saeki Kazuko, Shiraishi Hiroshi, Yoshimura Akihiko, Takaesu Giichi

Journal of Biological Chemistry 281 ( 48 ) 36683 - 36690 2006.12

ISSN 0021-9258

The transcription factor STAT3 is activated by interleukin-6-related cytokines and has been implicated as an oncogene; it promotes cell proliferation and is anti-apoptotic. However, in some cases, STAT3 has been shown to be pro-apoptotic, especially in mammary epithelial cells. In this report, we generated SOCS3-deficient murine embryonic fibroblasts (MEFs), in which STAT3 activation is extremely enhanced and prolonged. We found that LIF induces caspase-3 activation and apoptosis of SOCS3^-/- MEFs. Exogenous expression of the dominant negative form of STAT3 but not STAT1 suppressed LIF-induced apoptosis of SOCS3^-/- MEFs, indicating that STAT3 plays a critical role in apoptosis induction. As shown in mammary gland epithelial cells, expression of the phosphatidylinositol 3-kinase regulatory subunits p50α and p55α was induced in response to LIF in SOCS3^-/- MEFs but not in wild-type MEFs, and Akt/protein kinase B activity was substantially reduced in SOCS3^-/- MEFs. Furthermore, we found that some of the STAT3 target genes related to apoptosis and proliferation, such as Bcl-2 and cyclin D1, were repressed upon LIF treatment in SOCS3^-/- cells. Not only the up-regulation of p50α and p55α but also the repression of cyclin D1 and Bcl-2 in SOCS3^-/- MEFs was inhibited by dominant negative STAT3. These data suggest that prolonged activation of STAT3 could induce apoptosis/growth arrest rather than anti-apoptosis and proliferation in certain cases, and SOCS3 is a critical regulator of this balance. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

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Innate defense mechanism against virus infection within the cardiac myocyte requiring gp130-STAT3 signaling

Yajima Toshitaka, Yasukawa Hideo, Jeon Eun Seok, Xiong Dingding, Dorner Andrea, Iwatate Mitsuo, Nara Miwako, Zhou Hanbing, Summers-Torres Daphne, Hoshijima Masahiko, Chien Kenneth R., Yoshimura Akihiko, Knowlton Kirk U.

Circulation 114 ( 22 ) 2364 - 2373 2006.11

ISSN 0009-7322

BACKGROUND - Little is known about innate immune mechanisms within the cardiac myocyte that determine susceptibility to enterovirus infection, an important cause of myocarditis and subsequent heart failure. Although interferon (IFN) generally plays a key role in innate immunity, ablation of IFN receptors has little or no effect on acute coxsackievirus B3 infection in the heart. Interestingly, gp130-cytokine-mediated stimulation of neonatal ventricular myocytes has a cytoprotective effect against virus infection in culture that can be inhibited by suppressors of cytokine signaling (SOCS)-3, a physiological inhibitor of gp130 signaling that does not affect IFN signaling. Therefore, we hypothesized that inhibition of gp130 signaling by SOCS3 would change cardiac myocyte susceptibility to virus infection without affecting IFN signaling. METHODS AND RESULTS - We generated cardiac-specific SOCS3 transgenic mice. Despite an intact IFN-mediated antiviral response in adult transgenic myocytes, there was a marked increase in susceptibility to viral infection in the SOCS3 transgenic mouse hearts. This indicated the presence of IFN-independent innate defense mechanisms within the cardiac myocyte. Subsequently, we demonstrated that cardiac-specific gp130-knockout mice also had increased susceptibility to viral infection. Furthermore, we demonstrated that the gp130-mediated increase in survival of infected myocytes occurred through a signal transducers and activators of transcription-3-dependent mechanism that did not affect viral replication. This was accompanied by a persistent expression of full-length dystrophin after coxsackievirus B3 infection. In addition, we found that both SOCS3 transgenic and gp130-deficient mice had a decrease in α-sarcoglycan. CONCLUSIONS - SOCS3-mediated regulation of gp130 signaling can affect susceptibility to viral infection in the heart. Increased cardiac cell survival through gp130-signal transducers and activators of transcription-3 signaling appears to play an important role in preserving nondividing cardiac myocytes until specific immune responses begin to clear the virus. © 2006 American Heart Association, Inc.

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Two-sided roles of IL-27

Yoshimura Takeru, Takeda Atsunobu, Hamano Shinjiro, Miyazaki Yoshiyuki, Kinjyo Ichiko, Ishibashi Tatsuro, Yoshimura Akihiko, Yoshida Hiroki

Journal of Immunology 177 ( 8 ) 5377 - 5385 2006.10

ISSN 0022-1767

Recent lines of evidence have demonstrated that IL-27, a newly identified IL-12-related cytokine, has two apparently conflicting roles in immune responses: one as an initiator of Th1 responses and the other as an attenuator of inflammatory cytokine production. Although the BL-27-mediated Th1 initiation mechanism has been elucidated, little is known about the molecular basis for the suppression of cytokine production. In the present study, we demonstrated that IL-27 suppressed the production of various proinflammatory cytokines by fully activated CD4⁺ T cells while it had no effect on the cytokine production by CD4⁺ T cells at early phases of activation. IL-27 also suppressed IL-17 production by activated CD4⁺ T cells, thereby counteracting IL-23, another IL-12-related cytokine with proinflammatory effects. In fully activated CD4⁺ T cells, STAT3 was preferentially activated by IL-27 stimulation, whereas both STAT1 and 3 were activated by IL-27 in early activated CD4⁺ T cells. Lack of STAT3 in fully activated cells impaired the suppressive effects of IL-27. These data indicated that the preferential activation of STAT3 in fully activated CD4⁺ T cells plays an important role in the cytokine suppression by IL-27/WSX-1. Copyright © 2006 by The American Association of Immunologists, Inc.

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

Yoshida T., Hisamoto T., Akiba J., Koga H., Nakamura K., Tokunaga Y., Hanada S., Kumemura H., Maeyama M., Harada M., Ogata H., Yano H., Kojiro M., Ueno T., Yoshimura A., Sata M.

Oncogene 25 ( 45 ) 6056 - 6066 2006.10

ISSN 0950-9232

Aberrant activation of the Ras/Raf-1/extracellular-regulated kinase (ERK) pathway has been shown to be involved in the progression of human hepatocellular carcinoma (HCC). However, the mechanism of dysregulation of ERK activation is poorly understood. Recently, we identified Sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 domain (Spred) as a physiological inhibitor of the Ras/Raf-1/ERK pathway. In this study, we found that the expression levels of Spred-1 and -2 in human HCC tissue were frequently decreased, comparing with those in adjacent non-tumorous tissue. Moreover, Spred expression levels in HCC tissue were inversely correlated with the incidence of tumor invasion and metastasis. Forced expression of Spred-1 inhibited HCC cell proliferation in vitro and in vivo, which was associated with reduced ERK activation. Spred-1 overexpression also reduced the secretion of matrix metalloproteinase-9 (MMP-9) and MMP-2, which play important roles in tumor invasion and metastasis. In addition, Spred-1 inhibited growth factor-mediated HCC cell motility. These data indicate that the reduction of Spred expression in HCC is one of the causes of the acquisition of malignant features. Thus, Spred could be not only a novel prognostic factor but also a new therapeutic target for human HCC. © 2006 Nature Publishing Group. All rights reserved.

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ER stress-induced apoptosis and caspase-12 activation occurs downstream of mitochondrial apoptosis involving Apaf-1

Shiraishi Hiroshi, Okamoto Hideaki, Yoshimura Akihiko, Yoshida Hiroki

Journal of Cell Science 119 ( 19 ) 3958 - 3966 2006.10

ISSN 0021-9533

Accumulation of unfolded proteins induces endoplasmic reticulum (ER) stress. Excessive and prolonged stresses lead cells to apoptosis. However, the precise molecular mechanisms of ER stress-induced apoptosis have not been fully elucidated. We investigated the involvement of the apoptosome in ER stress-induced cell death pathway using mouse embryonic fibroblasts (MEFs) and mice deficient for Apaf-1. Apaf-1-deficient MEFs showed ore resistance to ER stress-inducing reagents as compared with wild type cells. Despite comparable induction of ER stress in both wild type and Apaf-1-deficient cells, activation of caspase-3 was only observed in wild type, but not Apaf-1-deficient, MEFs. Under ER stress conditions, BAX translocated to mitochondria and cytochrome c was released from mitochondria. We also demonstrated that caspase-12 was processed downstream of Apaf-1 and caspase-3, and neither overexpression nor knockdown of caspase-12 affected susceptibility of the cells to ER stress-induced cell death. Furthermore, in the kidneys of Apaf-1-deficient mice, apoptosis induced by in vivo administration of tunicamycin was remarkably suppressed as compared with wild type mice. These data collectively demonstrated that Apaf-1 and the mitochondrial pathway of apoptosis play significant roles in ER stress-induced apoptosis.

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Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system

Stumhofer Jason S., Laurence Arian, Wilson Emma H., Huang Elaine, Tato Cristina M., Johnson Leanne M., Villarino Alejandro V., Huang Qiulong, Yoshimura Akihiko, Sehy David, Saris Christiaan J M, O'Shea John J., Hennighausen Lothar, Ernst Matthias, Hunter Christopher A.

Nature Immunology 7 ( 9 ) 937 - 945 2006.09

ISSN 1529-2908

Studies have focused on the events that influence the development of interleukin 17 (IL-17)-producing T helper cells (T_H-17 cells) associated with autoimmunity, such as experimental autoimmune encephalitis, but relatively little is known about the cytokines that antagonize T_H-17 cell effector responses. Here we show that IL-27 receptor-deficient mice chronically infected with Toxoplasma gondii developed severe neuroinflammation that was CD4⁺ T cell dependent and was associated with a prominent IL-17 response. In vitro, treatment of naive primary T cells with IL-27 suppressed the development T_H-17 cells induced by IL-6 and transforming growth factor-β, which was dependent on the intracellular signaling molecule STAT1 but was independent of inhibition of IL-6 signaling mediated by the suppressor protein SOCS3. Thus IL-27, a potent inhibitor of T_H-17 cell development, may be a useful target for treating inflammatory diseases mediated by these cells.

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TGF-β1 suppresses IFN-γ-induced NO production in macrophages by suppressing STAT1 activation and accelerating iNOS protein degradation

Takaki Hiromi, Minoda Yasumasa, Koga Keiko, Takaesu Giichi, Yoshimura Akihiko, Kobayashi Takashi

Genes to Cells 11 ( 8 ) 871 - 882 2006.08

ISSN 1356-9597

TGF-β1 is a well-known immunosuppressive cytokine; however, little is known of the effect of TGF-β1 on antigen-presenting cells (APCs). In this report, we investigated the molecular mechanisms of the suppressive effects of TGF-β1 on APCs including dendritic cells and macrophages. Although TGF-β1 did not greatly affect the activation of APCs, as assessed by the induction of IL-12 or the upregulation of CD40 in response to LPS, it strongly inhibited IFN-γ-induced nitric oxide (NO) production from macrophages and dendritic cells. Using murine macrophage-like cell line RAW 264.7, we demonstrated that TGF-β1 not only reduced the inducible NO synthase (iNOS) protein stability but also suppressed the iNOS gene transcription. We also found that TGF-β1 directly inhibited IFN-γ-induced STAT1 activation by reducing STAT1 tyrosine phosphorylation. The IFN-γ Type I receptor (IFNGR1) was found to be associated with the TGF-β1 Type I receptor (TGF-βRI) and was phosphorylated by the TGF-βRI. Reduced activation of STAT1 by TGF-β1 was abrogated by the mutation in the IFNGR1 in which the serine residues of potential sites of phosphorylation by TGF-βRI were replaced by alanine residues. Thus, multiple mechanisms are present for the TGF-β1-mediated reduction of iNOS production, and we propose a novel mechanism for regulating inflammatory cytokine by an anti-inflammatory cytokine, TGF-β1; i.e. suppression of IFN-γ-induced STAT1 activation by an association of the IFNGR1 with the TGF-βRI. © 2006 The Authors Journal compilation © 2006 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.

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Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells

Kievit Paul, Howard Jane K., Badman Michael K., Balthasar Nina, Coppari Roberto, Mori Hiroyuki, Lee Charlotte E., Elmquist Joel K., Yoshimura Akihiko, Flier Jeffrey S.

Cell Metabolism 4 ( 2 ) 123 - 132 2006.08

ISSN 1550-4131

Suppressor of cytokine signaling-3 (Socs-3) negatively regulates the action of various cytokines, as well as the metabolic hormones leptin and insulin. Mice with haploinsufficiency of Socs-3, or those with neuronal deletion of Socs-3, are lean and more leptin and insulin sensitive. To examine the role of Socs-3 within specific neurons critical to energy balance, we created mice with selective deletion of Socs-3 within pro-opiomelanocortin (POMC)-expressing cells. These mice had enhanced leptin sensitivity, measured by weight loss and food intake after leptin infusion. On chow diet, glucose homeostasis was improved despite normal weight gain. On a high-fat diet, the rate of weight gain was reduced, due to increased energy expenditure rather than decreased food intake; glucose homeostasis and insulin sensitivity were substantially improved. These studies demonstrate that Socs-3 within POMC neurons regulates leptin sensitivity and glucose homeostasis, and plays a key role in linking high-fat diet to disordered metabolism. © 2006 Elsevier Inc. All rights reserved.

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Pigment epithelium-derived factor inhibits advanced glycation end product-induced retinal vascular hyperpermeability by blocking reactive oxygen species-mediated vascular endothelial growth factor expression

Yamagishi Sho Ichi, Nakamura Kazuo, Matsui Takanori, Inagaki Yosuke, Takenaka Katsuhiko, Jinnouchi Yuko, Yoshida Yumiko, Matsuura Tetsuro, Narama Isao, Motomiya Yoshihiro, Takeuchi Masayoshi, Inoue Hiroyoshi, Yoshimura Akihiko, Bucala Richard, Imaizumi Tsutomu

Journal of Biological Chemistry 281 ( 29 ) 20213 - 20220 2006.07

ISSN 0021-9258

Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis, suggesting that loss of PEDF contributes to proliferative diabetic retinopathy. However, the role of PEDF against retinal vascular hyperpermeability remains to be elucidated. We investigated here whether and how PEDF could inhibit the advanced glycation end product (AGE) signaling to vascular hyperpermeability. Intravenous administration of AGEs to normal rats not only increased retinal vascular permeability by stimulating vascular endothelial growth factor (VEGF) expression but also decreased retinal PEDF levels. Simultaneous treatments with PEDF inhibited the AGE-elicited VEGF-mediated permeability by down-regulating mRNA levels of p22^phox and gp91^phox, membrane components of NADPH oxidase, and subsequently decreasing retinal levels of an oxidative stress marker, 8- hydroxydeoxyguanosine. PEDF also inhibited the AGE-induced vascular hyperpermeability evaluated by transendothelial electrical resistance by suppressing VEGF expression. Furthermore, PEDF decreased reactive oxygen species (ROS) generation in AGE-exposed endothelial cells by suppressing NADPH oxidase activity via down-regulation of mRNA levels of p22^PHOX and gp91 ^PHOX. This led to blockade of the AGE-elicited Ras activation and NF-κB-dependent VEGF gene induction in endothelial cells. These results indicate that the central mechanism for PEDF inhibition of the AGE signaling to vascular permeability is by suppression of NADPH oxidase-mediated ROS generation and subsequent VEGF expression. Substitution of PEDF may offer a promising strategy for halting the development of diabetic retinopathy. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

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Deletion of the SOCS3 Gene in Liver Parenchymal Cells Promotes Hepatitis-Induced Hepatocarcinogenesis

Ogata Hisanobu, Kobayashi Takashi, Chinen Takatoshi, Takaki Hiromi, Sanada Takahito, Minoda Yasumasa, Koga Keiko, Takaesu Giichi, Maehara Yoshihiko, Iida Mitsuo, Yoshimura Akihiko

Gastroenterology 131 ( 1 ) 179 - 193 2006.07

ISSN 0016-5085

Background & Aims: A recent study has suggested that the methylation silencing of the suppressor of cytokine signaling-3 (SOCS3), a negative regulator of interleukin-6-related cytokines, could be involved in hepatocellular carcinoma (HCC). However, the roles of SOCS3 in hepatocellular carcinogenesis and hepatitis have not been established. We investigated the effect of deleting the SOCS3 gene on the development of hepatitis and HCC in hepatitis C virus-infected patients and mouse models. Methods: The expression of SOCS genes in HCC and non-HCC regions of patient samples was determined by real-time reverse-transcription polymerase chain reaction and immunoblotting. The conditional knockout approach in mice was used to determine the hepatocyte-specific roles of SOCS3. To generate a liver-specific deletion, floxed SOCS3 (SOCS3^fl/fl) mice were crossed with albumin-Cre transgenic mice. Hepatitis and HCC were induced by administering concanavalin A and diethylnitrosamine, respectively. Results: SOCS3 expression was reduced in the HCC regions compared with the non-HCC regions. Carcinogen-induced hepatic tumor development was enhanced by deletion of the SOCS3 gene, which was associated with higher levels of the targets of signal transducers and activators of transcription (ie, B-cell lymphoma-XL, B-cell lymphoma-2, C-myelocytomatosis, cyclin D1, and vascular endothelial growth factor). In the concanavalin A-mediated hepatitis model, deletion of the SOCS3 gene in the hepatocytes protected against liver injury through suppression of interferon-γ signaling and induction of the antiapoptotic protein Bcl-XL. Conclusions: Deletion of the SOCS3 gene in hepatocytes promotes the activation of STAT3, resistance to apoptosis, and an acceleration of proliferation, resulting in enhanced hepatitis-induced hepatocarcinogenesis. © 2006 American Gastroenterological Association Institute.

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Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury

Okada Seiji, Nakamura Masaya, Katoh Hiroyuki, Miyao Tamaki, Shimazaki Takuya, Ishii Ken, Yamane Junichi, Yoshimura Akihiko, Iwamoto Yukihide, Toyama Yoshiaki, Okano Hideyuki

Nature Medicine 12 ( 7 ) 829 - 834 2006.07

ISSN 1078-8956

In the injured central nervous system (CNS), reactive astrocytes form a glial scar and are considered to be detrimental for axonal regeneration, but their function remains elusive. Here we show that reactive astrocytes have a crucial role in wound healing and functional recovery by using mice with a selective deletion of the protein signal transducer and activator of transcription 3 (Stat3) or the protein suppressor of cytokine signaling 3 (Socs3) under the control of the Nes promoter-enhancer (Nes-Stat3^-/-, Nes-Socs3^-/-). Reactive astrocytes in Nes-Stat3^-/- mice showed limited migration and resulted in markedly widespread infiltration of inflammatory cells, neural disruption and demyelination with severe motor deficits after contusive spinal cord injury (SCI). On the contrary, we observed rapid migration of reactive astrocytes to seclude inflammatory cells, enhanced contraction of lesion area and notable improvement in functional recovery in Nes-Socs3^-/- mice. These results suggest that Stat3 is a key regulator of reactive astrocytes in the healing process after SCI, providing a potential target for intervention in the treatment of CNS injury. © 2006 Nature Publishing Group.

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SOCS1-negative feedback of STAT1 activation is a key pathway in the dsRNA-induced innate immune response of human keratinocytes

Dai Xiuju, Sayama Koji, Yamasaki Kenshi, Tohyama Mikiko, Shirakata Yuji, Hanakawa Yasushi, Tokumaru Sho, Yahata Yoko, Yang Lujun, Yoshimura Akihiko, Hashimoto Koji

Journal of Investigative Dermatology 126 ( 7 ) 1574 - 1581 2006.07

ISSN 0022-202X

Toll-like receptor (TLR)3 is a receptor for virus-associated double-stranded RNA, and triggers antiviral immune responses during viral infection. Epidermal keratinocytes express TLR3 and provide an innate immune defense against viral infection. Since the intracellular regulatory mechanism is unknown, we hypothesized that the signal transducers and activators of transcription (STAT)-suppressors of cytokine signaling (SOCS) system regulates the innate immune response of keratinocytes. Treatment with polyinosinic- polycytidylic acid (poly(I:C)) resulted in the rapid translocation of IFN regulatory factor (IRF)-3 into the nucleus, followed by phosphorylation of STAT1 and STAT3. The activation of STATs by poly(I:C) probably occurs in an indirect fashion, through poly(I:C)-induced IFN. We infected cells with the dominant-negative forms of STAT1 (STAT1F), STAT3 (STAT3F), and SOCS1 using adenovirus vectors. Infection with STAT1F suppressed the induction of macrophage inflammatory protein (MIP)-1α by poly(I:C), whereas STAT3F had a minimal effect, which indicates that STAT1 mediates MIP-1α induction. SOCS1, which is a negative feedback regulator of STAT1 signaling, was induced by treatment with poly(I:C). SOCS1 infection inhibited the phosphorylation of STAT1 and significantly reduced poly(I:C)-induced MIP-1α production. Furthermore, STAT1-SOCS1 regulated poly(I:C)-induced TLR3 and IRF-7 expression. However, SOCS1 did not affect NF-κB signaling. Thus, the STAT1-SOCS1 pathway regulates the innate immune response via TLR3 signaling in epidermal keratinocytes. © 2006 The Society for Investigative Dermatology.

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IFNγ-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice

Hanada Toshikatsu, Kobayashi Takashi, Chinen Takatoshi, Saeki Kazuko, Takaki Hiromi, Koga Keiko, Minoda Yasumasa, Sanada Takahito, Yoshioka Tomoko, Mimata Hiromitsu, Kato Seiya, Yoshimura Akihiko

Journal of Experimental Medicine 203 ( 6 ) 1391 - 1397 2006.06

ISSN 0022-1007

Approximately 20% of human cancers are estimated to develop from chronic inflammation. Recently, the NF-κB pathway was shown to play an essential role in promoting inflammation-associated cancer, but the role of the JAK/STAT pathway, another important signaling pathway of proinflammatory cytokines, remains to be investigated. Suppressor of cytokine signaling-1 (SOCS1) acts as an important physiological regulator of cytokine responses, and silencing of the SOCS1 gene by DNA methylation has been found in several human cancers. Here, we demonstrated that SOCS1-deficient mice (SOCS1^-/-Tg mice), in which SOCS1 expression was restored in T and B cells on a SOCS1^-/- background, spontaneously developed colorectal carcinomas carrying nuclear β-catenin accumulation and p53 mutations at 6 months of age. However, interferon (IFN)γ^-/-SOCS1^-/- mice and SOCS1 ^-/-Tg mice treated with anti-IFNγ antibody did not develop such tumors. STAT3 and NF-κB activation was evident in SOCS1^-/-Tg mice, but these were not sufficient for tumor development because these are also activated in IFNγ^-/-SOCS1^-/- mice. However, colons of SOCS1^-/-Tg mice, but not IFNγ^-/-SOCS1 ^-/- mice, showed hyperactivation of STAT1, which resulted in the induction of carcinogenesis-related enzymes, cyclooxygenase-2 and inducible nitric oxide synthase. These data strongly suggest that SOCS1 is a unique antioncogene which prevents chronic inflammation-mediated carcinogenesis by regulation of the IFNγ/STAT1 pathways. JEM © The Rockefeller University Press.

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A novel Zinc finger protein, ZCCHC11, interacts with TIFA and modulates TLR signaling

Minoda Yasumasa, Saeki Kazuko, Aki Daisuke, Takaki Hiromi, Sanada Takahito, Koga Keiko, Kobayashi Takashi, Takaesu Giichi, Yoshimura Akihiko

Biochemical and Biophysical Research Communications 344 ( 3 ) 1023 - 1030 2006.06

ISSN 0006-291X

Toll-like receptors (TLRs) play an important role as a sensor of microbial pathogens in the innate immune response. TLRs transmit signals through the recruitment of adaptor proteins including tumor necrosis factor-associated factor 6 (TRAF6), which mediates the activation of IκB kinase (IKK). TIFA (TRAF-interacting protein with a forkhead-associated (FHA) domain) has been shown to bind to TRAF6 and activate IKK by promoting the oligomerization and ubiquitin-ligase activity of TRAF6. FHA domains preferentially bind to phospho-threonine residues in their targets. Here, we identified a novel zinc finger protein, ZCCHC11, that interacts with TIFA from phosphoproteins of a macrophage cell line, RAW 264.7, by using affinity purification with GST-TIFA and mass spectrometric analysis. By a search of the EST database, we found a 200 kDa full-length form (ZCCHC11L). ZCCHC11L was mostly located to the nucleus, but translocated into the cytoplasm in response to LPS and bound to TIFA. Overexpression and knockdown by siRNA indicated that ZCCHC11 functions as a negative regulator of TLR-mediated NF-κB activation. The N-terminal region (ZCCHC11S) including CCHC-type Zn-finger motif was sufficient for suppression of NF-κB. We propose that ZCCHC11 is a unique TLR signal regulator, which interacts with TIFA after LPS treatment and suppresses the TRAF6-dependent activation of NF-κB. © 2006 Elsevier Inc. All rights reserved.

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Signal transduction of inflammatory cytokines and tumor development

Yoshimura Akihiko

Cancer Science 97 ( 6 ) 439 - 447 2006.06

ISSN 1347-9032

It has been estimated that >20% of all malignancies are initiated or exacerbated by inflammation. Until recently, the molecular basis of this process has not been clarified. However, recent studies have uncovered the molecular mechanism of intracellular signaling pathways of inflammatory cytokines such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-6. Three major transcription factors including NF-κB, STAT1 and STAT3 have been shown to play major roles in transmitting inflammatory cytokine signals to the nucleus. One function of NF-κB and STAT3 in tumor cells is the promotion of cell growth and cell survival through the induction of target genes, whose products promote cell division and inhibit apoptosis. In addition, NF-κB and STAT1 are important transcription factors that induce inflammatory mediators from inflammatory cells, especially macrophages, while STAT3 often antagonizes this process. STAT1 is generally believed to be an anti-oncogene because it promotes apoptosis through p53, but it could promote inflammation-mediated tumor development by enhancing tissue injury, remodeling, fibrosis and inflammation. Hence, the inhibition of NF-κB and STATs offers a strategy for treatment of a variety of malignancies and can convert inflammation-induced tumor growth into inflammation-induced tumor regression. © 2006 Japanese Cancer Association.

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