Details of a Researcher - Yoshimura, Akihiko

Papers - Yoshimura, Akihiko

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Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells

Chen Zhi, Laurence Arian, Kanno Yuka, Pacher-Zavisin Margit, Zhu Bing Mei, Tato Cristina, Yoshimura Akihiko, Hennighausen Lothar, O'Shea John J.

Proceedings of the National Academy of Sciences of the United States of America 103 ( 21 ) 8137 - 8142 2006.05

ISSN 0027-8424

Suppressor of cytokine signaling (Socs) 3 is a cytokine-inducible inhibitor with critical but selective cell-specific effects. We show that deficiency of Socs3 in T cells had minimal effects on differentiation of T cells to the T helper (Th) 1 or Th2 subsets; accordingly, Socs3 had no effect on IL-12-dependent signal transducer and activator of transcription (Stat) 4 phosphorylation or IL-4-dependent Stat6 phosphorylation. By contrast, Socs3 was found to be a major regulator of IL-23-mediated Stat3 phosphorylation and Th17 generation, and Stat3 directly binds to the IL-17A and IL-17F promoters. We conclude that Socs3 is an essential negative regulator of IL-23 signaling, inhibition of which constrains the generation of Th17 differentiation. © 2006 by The National Academy of Sciences of the USA.

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The neuropeptide neuromedin U activates eosinophils and is involved in allergen-induced eosinophilia

Moriyama Maiko, Fukuyama Satoru, Inoue Hiromasa, Matsumoto Takafumi, Sato Takahiro, Tanaka Kentaro, Kinjyo Ichiko, Kano Tatsuhiko, Yoshimura Akihiko, Kojima Masayasu

American Journal of Physiology - Lung Cellular and Molecular Physiology 290 ( 5 ) 2006.05

ISSN 1040-0605

Neuromedin U (NMU) is a neuropeptide expressed not only in the central nervous system but also in various organs, including the gastrointestinal tract and lungs. NMU interacts with two G protein-coupled receptors, NMU-R1 and NMU-R2. Although NMU-R2 is expressed in a specific region of the brain, NMU-R1 is expressed in various peripheral tissues, including immune and hematopoietic cells. Our recent study demonstrated an important role of NMU in mast cell-mediated inflammation. In this study, we showed that airway eosinophilia was reduced in NMU-deficient mice in an allergen-induced asthma model. There were no differences in the antigen-induced Th2 responses between wild-type and NMU knockout mice. NMU-R1 was highly expressed in the eosinophil cell line, and NMU directly induced Ca²⁺ mobilization and extracellular/signal- regulated kinase phosphorylation. NMU also induced cell adhesion to components of the extracellular matrix (fibronectin and collagen type I), and chemotaxis in vitro. Furthermore, NMU-R1 was also expressed in human peripheral blood eosinophils, and NMU induced cell adhesion in a dose-dependent manner. These data indicate that NMU promotes eosinophil infiltration into inflammatory sites by directly activating eosinophils. Our study suggests that NMU receptor antagonists could be novel targets for pharmacological inhibition of allergic inflammatory diseases, including asthma. Copyright © 2006 the American Physiological Society.

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Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-β1 production

Ogata H., Chinen T., Yoshida T., Kinjyo I., Takaesu G., Shiraishi H., Iida M., Kobayashi T., Yoshimura A.

Oncogene 25 ( 17 ) 2520 - 2530 2006.04

ISSN 0950-9232

Recently, DNA methylation and reduced expression of the suppressor of the cytokine signaling-3 (SOCS3) gene in human hepatocellular carcinoma (HCC) patients have been reported. However, the roles of SOCS3 in HCC development in vivo have not been clarified. Using RT-PCR analysis and Western blotting, we confirmed that SOCS3 expression was reduced in HCC patients. However, reduced expression of SOCS3 occurred not only in HCC but also in nontumor regions, and this reduction was stronger as the fibrosis grade increased. Furthermore, SOCS3 levels were inversely correlated with signal transducers and activators of transcription-3 (STAT3) activation as well as transforming growth factor (TGF)-β1 levels in the non-HCC region. To define the molecular consequences of SOCS3 silencing/STAT3 hyperactivation and liver fibrosis, we examined liver-specific SOCS3-deficient mice. We demonstrated that SOCS3 deletion in the liver resulted in hyperactivation of STAT3 and promoted ConA- and chemical-induced liver fibrosis. The expression of TGF-β1, a mediator of fibrosis, was enhanced by SOCS3 gene deletion, but suppressed by the overexpression of a dominant-negative STAT3 or SOCS3 both in vivo and in vitro. These data suggest that TGF-β1 is a target gene of STAT3 and could be one of the mechanisms for enhanced fibrosis in SOCS3-deficient mice. Thus, our present study provides a novel role of SOCS3 and STAT3 in HCC development: in addition to the previously characterized oncogenic potentials, STAT3 enhances hepatic fibrosis through the upregulation of TGF-β1 expression, and SOCS3 prevents this process. © 2006 Nature Publishing Group All rights reserved.

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Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor-β1

Kinjyo Ichiko, Inoue Hiromasa, Hamano Shinjiro, Fukuyama Satoru, Yoshimura Takeru, Koga Keiko, Takaki Hiromi, Himeno Kunisuke, Takaesu Giichi, Kobayashi Takashi, Yoshimura Akihiko

Journal of Experimental Medicine 203 ( 4 ) 1021 - 1031 2006.04

ISSN 0022-1007

Suppressor of cytokine signaling (SOCS)3 is a major negative feedback regulator of signal transducer and activator of transcription (STAT)3-activating cytokines. Transgenic mouse studies indicate that high levels of SOCS3 in T cells result in type 2 T helper cell (Th2) skewing and lead to hypersensitivity to allergic diseases. To define the physiological roles of SOCS3 in T cells, we generated T cell-specific SOCS3 conditional knockout mice. We found that the mice lacking SOCS3 in T cells showed reduced immune responses not only to ovalbumin-induced airway hyperresponsiveness but also to Leishmania major infection. In vitro, SOCS3-deficient CD4⁺ T cells produced more transforming growth factor (TGF)-β1 and interleukin (IL)-10, but less IL-4 than control T cells, suggesting preferential Th3-like differentiation. We found that STAT3 positively regulates TGF-β1 promoter activity depending on the potential STAT3 binding sites. Furthermore, chromatin immunoprecipitation assay revealed that more STAT3 was recruited to the TGF-β1 promoter in SOCS3-deficient T cells than in control T cells. The activated STAT3 enhanced TGF-β1 and IL-10 expression in T cells, whereas the dominant-negative form of STAT3 suppressed these. From these findings, we propose that SOCS3 regulates the production of the immunoregulatory cytokines TGF-β1 and IL-10 through modulating STAT3 activation. © The Rockefeller University Press.

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The neuropeptide neuromedin U promotes IL-6 production from macrophages and endotoxin shock

Moriyama Maiko, Matsukawa Akihiro, Kudoh Shinji, Takahashi Tomoko, Sato Takahiro, Kano Tatsuhiko, Yoshimura Akihiko, Kojima Masayasu

Biochemical and Biophysical Research Communications 341 ( 4 ) 1149 - 1154 2006.03

ISSN 0006-291X

Neuromedin U (NMU) is a neuropeptide involved in appetite, circadian rhythm, and pronociception. However, the NMU receptor NMU-R1 has been shown to be expressed in immune cells and NMU promotes mast cell-dependent inflammation. In this study, we demonstrated that NMU plays an important role in IL-6 production in macrophages. NMU-deficient mice were resistant against cecal ligation puncture- as well as LPS-induced septic shock. IL-6 but not TNF-α levels were markedly reduced in LPS-treated NMU-deficient mice compared with wild type mice. Both NMU and NMU-R1 were expressed in wild type peritoneal macrophages, and treatment with LPS resulted in up-regulation of NMU but down-regulation of NMU-R1 expression, however, no down-regulation of NMU-R1 was observed in NMU-deficient macrophages where LPS-induced IL-6 production was severely reduced. These data suggest that LPS-induced IL-6 expression is partly dependent on autocrine/paracrine activation of the NMU-NMU-R1 signals in macrophages. © 2006 Elsevier Inc. All rights reserved.

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Divergent mechanisms utilized by SOCS3 to mediate interleukin-10 inhibition of tumor necrosis factor α and nitric oxide production by macrophages

Qasimi Pooran, Ming-Lum Andrew, Ghanipour Ali, Ong Christopher J., Cox Michael E., Ihle James, Cacalano Nicolas, Yoshimura Akihiko, Mui Alice L F

Journal of Biological Chemistry 281 ( 10 ) 6316 - 6324 2006.03

ISSN 0021-9258

The cytokine interleukin-10 (IL-10) potently inhibits macrophage function through activation of the transcription factor STAT3. The expression of SOCS3 (suppressor of cytokine signaling-3) has been shown to be induced by IL-10 in a STAT3-dependent manner. However, the relevance of SOCS3 expression to the anti-inflammatory effect of IL-10 on macrophages has been controversial. Through kinetic analysis of the requirement for SOCS3 in IL-10 inhibition of lipopolysaccharide (LPS)-stimulated tumor necrosis factor-α (TNFα) transcription and translation, SOCS3 was found to be necessary for TNFα expression during the early phase, but not the late phase of IL-10 action. SOCS3 was essential for IL-10 inhibition of LPS-stimulated production of iNOS (inducible nitricoxide synthase) protein and nitric oxide (NO). To determine the domains of SOCS3 protein important in mediating these effects, SOCS3 ^-/- macrophages were reconstituted with SOCS3 mutated for the SH2, KIR, SOCS box domains, and tyrosines 204 (Tyr²⁰⁴) and 221 (Tyr ²²¹). The SH2 domain, SOCS box, and both Tyr²⁰⁴ and Tyr²²¹ were required for IL-10 inhibition of TNFα mRNA and protein expression, but interestingly the KIR domain was necessary only for IL-10 inhibition of TNFα protein expression. In contrast, Tyr ²⁰⁴ and Tyr²²¹ were the only structural features of SOCS3 that were necessary in mediating IL-10 inhibition of iNOS protein expression and NO production. These data define SOCS3 as an important mediator of IL-10 inhibition of macrophage activation and that SOCS3 interferes with distinct LPS-stimulated signal transduction events through differing mechanisms. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

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Involvement of a novel Q-SNARE, D12, in quality control of the endomembrane system

Okumura Akiko Joo, Hatsuzawa Kiyotaka, Tamura Taku, Nagaya Hisao, Saeki Kazuko, Okumura Fumihiko, Nagao Kenji, Nishikawa Mitsuo, Yoshimura Akihiko, Wada Ikuo

Journal of Biological Chemistry 281 ( 7 ) 4495 - 4506 2006.02

ISSN 0021-9258

The cellular endomembrane system requires the proper kinetic balance of synthesis and degradation of its individual components, which is maintained in part by a specific membrane fusion apparatus. In this study, we describe the molecular properties of D12, which was identified from a mouse expression library. This C-terminal anchored membrane protein has sequence similarity to both a yeast soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE), Use1p/Slt1p, and a recently identified human syntaxin 18-binding protein, p31. D12 formed a tight complex with syntaxin 18 as well as Sec22b and bound to α-SNAP, indicating that D12 is a SNARE protein. Although the majority of D12 is located in the endoplasmic reticulum and endoplasmic reticulum-Golgi intermediate compartments at steady state, overexpression or knockdown of D12 had no obvious effects on membrane trafficking in the early secretory pathway. However, suppression of D12 expression caused rapid appearance of lipofuscin granules, accompanied by apoptotic cell death without the apparent activation of the unfolded protein response. The typical cause of lipofuscin formation is the impaired degradation of mitochondria by lysosomal degradative enzymes, and, consistent with this, we found that proper post-Golgi maturation of cathepsin D was impaired in D12-deficient cells. This unexpected observation was supported by evidence that D12 associates with VAMP7, a SNARE in the endosomallysosomal pathway. Hence, we suggest that D12 participates in the degradative function of lysosomes. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

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Suppressor of cytokine signaling-1 regulates inflammatory bowel disease in which both IFNγ and IL-4 are involved

Chinen Takatoshi, Kobayashi Takashi, Ogata Hisanobu, Takaesu Giichi, Takaki Hiromi, Hashimoto Masayuki, Yagita Hideo, Nawata Hajime, Yoshimura Akihiko

Gastroenterology 130 ( 2 ) 373 - 388 2006.02

ISSN 0016-5085

Background & Aims: The suppressor of cytokine signaling-1 (SOCS1) is a potent negative regulator of various cytokines and it has been implicated in the regulation of immune responses. However, the role of SOCS1 in inflammatory bowel diseases (IBDs) has not been clarified. To determine the role of SOCS1 in colitis, we generated SOCS1/T-cell receptor α (TCRα) double knockout (DKO) mice. Methods: The depletion of interferon γ (IFNγ) and IL-4 was achieved by crossing the DKO mice with IFNγ knockout (KO) mice and by the administration of anti-IL-4 antibody, respectively. The activation of cytokine-induced transcription factors was determined by Western blotting with phosphorylation-specific antibodies, and the induction of inflammatory factors was measured by reverse-transcription polymerase chain reaction. Results: Much more severe colitis developed in 100% of the DKO mice within 9 weeks of age than in TCRα-KO mice. Although the proportion and the activation status of CD4⁺ TCRα^-β⁺ T cells in DKO mice were similar to those in TCRα-KO mice, signal transducer and activator of transcription 1, nuclear factor κB, and their target genes were hyperactivated in infiltrated mononuclear cells and colonic epithelial cells in DKO mice. Cytokine-depletion experiments showed that exacerbated colitis in the DKO mice was dependent on both IFNγ and IL-4. SOCS1-deficient cells were hypersensitive to IFNγ, IL-4, and lipopolysaccharides, depending on the target genes. Conclusions: SOCS1 plays an important role in preventing murine colitis by restricting the cytokine signals. SOCS1/TCRα DKO mice could be a useful model for investigating human IBD. © 2006 by the American Gastroenterological Association.

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Mal-function of TLRs by SOCS

Kobayashi Takashi, Takaesu Giichi, Yoshimura Akihiko

Nature Immunology 7 ( 2 ) 123 - 124 2006.02

ISSN 1529-2908

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Suppressor of cytokine signalling 1 in lymphocytes regulates the development of intestinal inflammation in mice

Inagaki-Ohara K., Sasaki A., Matsuzaki G., Ikeda T., Hotokezaka M., Chijiiwa K., Kubo M., Yoshida H., Nawa Y., Yoshimura A.

Gut 55 ( 2 ) 212 - 219 2006.02

ISSN 0017-5749

Background and aims: Imbalance between pro- and anti-inflammatory cytokines produced by intestinal T cells induces inflammatory bowel diseases (IBD). However, the importance of regulation of cytokine signalling in IBD has not been fully clarified. We have demonstrated that suppressor of cytokine signalling 1 (SOCS1) is expressed in inflamed tissues in an experimental colitis model. In the present study, we investigated the role of SOCS1 in colitis models to clarify the mechanism of IBD development. Methods: Intestinal T cells in transgenic mice expressing high levels of SOCS1 in lymphocytes (SOCS1Tg mice) were characterised by flow cytometric analysis and cytokine production from intestinal T cells was determined by ELISA. 2,4,6-Trinitrobenzene sulphonic acid (TNBS) induced colitis was induced in SOCS1Tg mice and severity was compared with control littermates by measurement of survival rates, Intracellular signalling was assessed by western blotting analysis. Results: SOCS1Tg mice developed colitis spontaneously with age. Young SOCS1Tg mice less than 15 weeks of age, before the onset of colitis, were susceptible to TNBS induced colitis. Intestinal T cells of SOCS1Tg mice showed increased interferon γ and tumour necrosis factor a production and decreased transforming growth factor γ production. Expression of cytotoxic T lymphocyte associated antigen 4 (CTLA-4), a negative regulator of T cell activation, in SOCS1Tg mice was severely impaired at the protein level although mRNA levels of CTLA-4 in SOCS1Tg mice were comparable with those in control mice. Conclusions: Our data suggest that SOCS1 plays an important role in the regulation of colitis by controlling intestinal T cell activation mediated through CTLA-4 expression.

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Computer simulation of the role of SOCS family protein in helper T cell differentiation

Yamada Satoshi, Tsukada Jun, Yoshimura Akihiko, Kubo Masato

International Immunology 18 ( 2 ) 335 - 345 2006.02

ISSN 0953-8178

The T_h1/T_h2 balance determines the nature of an immune response, and particular cytokines, IL-4 and IL-12, determine the direction at the initial stage of activation through TCRs. To investigate how cytokine networks and related signaling pathways impact upon the T_h1/T_h2 balance, we have developed a computer model for the simulation of T_h differentiation. The model includes the IL-4, IL-12 and IFN-γ signal transduction pathways, a positive and negative feedback mechanism for cytokine signaling and cytokine-induced negative regulators such as suppressors of cytokine signaling (SOCS)1, SOCS3 and SOCS5. In the present study, we propose a 'T_h0 model', in which naive T cells differentiate neither into T_h1 nor into T_h2 states in unskewed cytokine conditions. The model was found to be consistent with experimental results in BALB/c mice. The results of in silico analysis in the condition with SOCS- and signal transducer and activator of transcription (STAT) family-deficient and transgenic states were well fitted to ex vivo experimental results for T_h1 and T_h2 differentiation profiles in the deficient and transgenic mice. The T_h0 model suggested the possibility that dominant T_h1 differentiation in STAT4/STAT6 double-deficient mice may be due to a positive feedback effect of initial IFN-γ production from T cells. The in silico assessment of beneficial effects of inhibitory drugs by simulation analysis with our T_h0 model indicated that Janus kinase 3-specific inhibitors might be suitable candidates for the modification of T_h2-dominant immune responses. Our results demonstrate that models for the simulation of signaling network, such as our T_h0 model, are useful tools for the in silico evaluation of novel drug candidates. © The Author Society for Immunology. 2006. All rights reserved.

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Association study of polymorphisms in SOCS family genes with type 1 diabetes mellitus

Ni R., Ihara K., Miyako K., Takemoto M., Ishimura M., Kohno H., Matsuura N., Yoshimura A., Hara T.

International Journal of Immunogenetics 33 ( 1 ) 7 - 10 2006.02

ISSN 1744-3121

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Suppression of IL-6 production and proliferation by blocking STAT3 activation in malignant soft tissue tumor cells

Shouda Takanori, Hiraoka Koji, Komiya Setsuro, Hamada Tetsuya, Zenmyo Michihisa, Iwasaki Hiroshi, Isayama Teruto, Fukushima Nobuhiro, Nagata Kensei, Yoshimura Akihiko

Cancer Letters 231 ( 2 ) 176 - 184 2006.01

ISSN 0304-3835

There is no established optimum treatment for malignant fibrous histiocytoma (MFH) at present, and few MFH cell lines are established. In the present study, we established new MFH cell lines, KHZ-MFH and SFT85-03, and investigated the JAK/STAT (Janus kinase/signal transducer and activator of transcription) signaling pathway. We found that MFH cells secreted high levels of IL-6 and that STAT3 was constitutively activated in these cells. The JAK2 kinase inhibitor, tyrphostin AG490, suppressed the growth of MFH cells and inhibited the secretion of IL-6. Furthermore, blockade of activated STAT3 by forced expression of a cytokine signaling repressor, SOCS3 gene as well as a dominant-negative STAT3 in these cells significantly suppressed their growth. These results indicated that an autocrine mechanism of the JAK/STAT3 signaling pathway could promote the growth of MFH cells and that this pathway could be a therapeutic target of MFH. © 2005 Elsevier Ireland Ltd. All rights reserved.

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Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages

Sekine Yuichi, Yumioka Taro, Yamamoto Tetsuya, Muromoto Ryuta, Imoto Seiyu, Sugiyma Kenji, Oritani Kenji, Shimoda Kazuya, Minoguchi Mayu, Akira Shizuo, Yoshimura Akihiko, Matsuda Tadashi

Journal of Immunology 176 ( 1 ) 380 - 389 2006.01

ISSN 0022-1767

Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains pleckstrin and Src homology 2-like domains as well as a YXXQ motif in its C-terminal region. Our previous studies have demonstrated that STAP-2 binds to STAT3 and STAT5, and regulates their signaling pathways. In the present study, STAP-2 was found to positively regulate LPS/TLR4-mediated signals in macrophages. Disruption of STAP-2 resulted in impaired LPS/TLR4-induced cytokine production and NF-κB activation. Conversely, overexpression of STAP-2 enhanced these LPS/TLR4-induced biological activities. STAP-2, particularly its Src homology 2-like domain, bound to both MyD88 and IκB kinase (IKK)-αβ, but not TNFR-associated factor 6 or IL-1R-associated kinase 1, and formed a functional complex composed of MyD88-STAP-2-IKK-αβ. These interactions augmented MyD88- and/or IKK-αβ-dependent signals, leading to enhancement of the NF-κB activity. These results demonstrate that STAP-2 may constitute an alternative LPS/TLR4 pathway for NF-κB activation instead of the TNFR-associated factor 6-IL-1R-associated kinase 1 pathway. Copyright © 2005 by The American Association of Immunologists, Inc.

FLN29, a novel interferon- and LPS-inducible gene acting as a negative regulator of toll-like receptor signaling

Mashima Ryuichi, Saeki Kazuko, Aki Daisuke, Minoda Yasumasa, Takaki Hiromi, Sanada Takahito, Kobayashi Takashi, Aburatani Hiroyuki, Yamanashi Yuji, Yoshimura Akihiko

Journal of Biological Chemistry 280 ( 50 ) 41289 - 41297 2005.12

ISSN 0021-9258

Lipopolysaccharide (LPS) activates macrophages through toll-like receptor (TLR) 4. Although the mechanism of the TLR signaling pathway has been well documented, the mechanism of the negative regulation in response to LPS, particularly LPS tolerance, is still poorly understood. In this study we identified and characterized a novel interferon- and LPS-inducible gene, FLN29, which contains a TRAF6-related zinc finger motif and TRAF family member-associated NF-κB activator-related sequences. The induction of FLN29 was dependent on STAT1. The forced expression of FLN29 in macrophage-like RAW cells resulted in the suppression of TLR-mediated NF-κB and mitogen-activated protein kinase activation, while a reduced expression of FLN29 by small interfering RNA partly cancelled the down-regulation of LPS signaling. Furthermore, we demonstrated that NF-κB activation induced by TRAF6 and TAB2 was impaired by co-expression of FLN29, suggesting FLN29 may regulate the downstream of TRAF6. Taken together, FLN29 is a new negative feedback regulator of TLR signaling. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

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SOCS genes

Yoshimura Akihiko, Nishinakamura Hitomi, Takaki Hiromi

International Congress Series 1285 121 - 129 2005.11

ISSN 0531-5131

Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. Many of these cytokines exert their biological functions through Janus tyrosine kinases (JAKs) and STAT transcription factors. The CIS (cytokine-inducible SH2 protein) and SOCS (suppressors of cytokine signaling) are a family of intracellular proteins, several of which have emerged as key physiological regulators of cytokine-mediated homeostasis, including innate and adaptive immunity. We investigated the roles of suppressors of cytokine signaling (SOCSs) in regulating dendritic cell (DC) maturation and function. We showed that SOCS1-deficient DCs induced stronger Th1-type responses both in vitro and in vivo. SOCS1-deficient DCs induced higher interferon-γ (IFNγ) production from naive T cells than wild-type DCs in vitro. Lymph node T cells also produced higher amount of IFNγ when SOCS1-deficient bone marrow-derived (BM) DCs were transferred in vivo. Moreover, SOCS1^-/- BMDCs raised more effective anti-tumor immunity than wild-type BMDCs. On the other hand, SOCS3-deficeint BMDCs expressed lower levels of MHC, co-stimulators and CD40 in response to LPS. SOCS3-deficient DCs induced lower T cell responses. Thus, SOCS1 and SOCS3 reciprocally regulate DC maturation. © 2005.

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Induction of keratinocyte migration via transactivation of the epidermal growth factor receptor by the antimicrobial peptide LL-37

Tokumaru Sho, Sayama Koji, Shirakata Yuji, Komatsuzawa Hitoshi, Ouhara Kazuhisa, Hanakawa Yasushi, Yahata Yoko, Dai Xiuju, Tohyama Mikiko, Nagai Hiroshi, Yang Lujun, Higashiyama Shigeki, Yoshimura Akihiko, Sugai Motoyuki, Hashimoto Koji

Journal of Immunology 175 ( 7 ) 4662 - 4668 2005.10

ISSN 0022-1767

The closure of skin wounds is essential for resistance against microbial pathogens, and keratinecyte migration is an important step in skin wound healing. Cathelicidin hCAP18/LL-37 is an innate antimicrobial peptide that is expressed in the skin and acts to eliminate microbial pathogens. Because hCAP18/LL-37 is up-regulated at skin wound sites, we hypothesized that LL-37 induces keratinocyte migration. In this study, we found that 1 μg/ml LL-37 induced the maximum level of keratinocyte migration in the Boyden chamber assay. In addition, LL-37 phosphorylated the epidermal growth factor receptor (EGFR) after 10 min, which suggests that LL-37-induced keratinocyte migration occurs via EGFR transactivation. To test this assumption, we used inhibitors that block the sequential steps of EGFR transactivation, such as OSU8-1, CRM197, anti-EGFR no. 225 Ab, and AG1478. All of these inhibitors completely blocked LL-37-induced keratinocyte migration, which indicates that migration occurs via HB-EGF-mediated EGFR transactivation. Furthermore, CRM197, anti-EGFR no. 225, and AG1478 blocked the LL-37-induced phosphorylation of STAT3, and transfection with a dominant-negative mutant of STAT3 abolished LL-37-induced keratinocyte migration, indicating the involvement of the STAT3 pathway downstream of EGFR transactivation. Finally, we tested whether the suppressor of cytokine signaling (SOCS)/cytokine-inducible Src homology 2-containing protein (CIS) family of negative regulators of STAT3 regulates LL-37-induced keratinocyte migration. Transfection with SOCS1/Jak2 binding protein or SOCS3/CIS3 almost completely abolished LL-37-induced keratinocyte migration. In conclusion, LL-37 induces keratinocyte migration via heparin-binding-EGF-mediated transactivation of EGFR, and SOCS1/Jak2 binding and SOCS3/CIS3 negatively regulate this migration. The results of this study suggest that LL-37 closes skin wounds by the induction of keratinocyte migration. Copyright © 2005 by The American Association of Immunologists, Inc.

The role of suppressor of cytokine signaling 1 as a negative regulator for aberrant expansion of CD8α⁺ dendritic cell subset

Tsukada Jun, Ozaki Akemi, Hanada Toshikatsu, Chinen Takatoshi, Abe Ryo, Yoshimura Akihiko, Kubo Masato

International Immunology 17 ( 9 ) 1167 - 1178 2005.09

ISSN 0953-8178

The suppressor of cytokine signaling (SOCS) 1 is a negative regulator in multiple cytokine-related aspects to maintain immunological homeostasis. Here, we studied a role of SOCS1 on dendritic cell (DC) maturation in the mice lacking either TCRα chain or CD28 in SOCS1-deficient background, and found that the SOCS1 could restore acute phase of inflammatory response in SOCS1-deficient mice. The CD11c⁺ CD8^- DC population in freshly isolated splenic DCs from normal mice highly expressed SOCS1. However, in SOCS1-deficient environment, the proportion of CD8α⁺ DCs (CD8 DCs) noticeably increased without affecting the cell number of conventional and plasmacytoid DC populations. This population revealed the CD11c^dull CD8α⁺ CD11b^- CD45RA^- B220^- phenotype, which is a minor population in normal mice. Localization of the abnormal CD8 DCs in splenic microenvironments was mainly restricted to deep within red pulp. The CD8 DCs secrete a large amount of IFN-γ, IL-12 and B lymphocyte stimulator/B cell activation factor of the tumor necrosis factor family in response to LPS and CpG stimulation. This is responsible for the development of DC-mediated systemic autoimmunity in the old age of SOCS1-deficient mice. Moreover, the CD8 DC subsets expressed more indoleamine 2,3-dioxygenase and IL-10, and hence inhibit the allogeneic proliferative T cell response and antigen-induced T_h1 responses. Therefore, SOCS1 expression during DC maturation plays a role in surveillance in controlling the aberrant expansion of abnormal DC subset to maintain homeostasis of immune system. © The Japanese Society for Immunology. 2005. All rights reserved.

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The Sprouty-related protein, Spred-1, localizes in a lipid raft/caveola and inhibits ERK activation in collaboration with caveolin-1

Nonami Atsushi, Taketomi Takaharu, Kimura Akiko, Saeki Kazuko, Takaki Hiromi, Sanada Takahito, Taniguchi Koji, Harada Mine, Kato Reiko, Yoshimura Akihiko

Genes to Cells 10 ( 9 ) 887 - 895 2005.09

ISSN 1356-9597

Caveolin-1 (Cav-1) has been suggested to function as a negative regulator of mitogen-stimulated proliferation and the Ras-p42/44 ERK (MAP kinase) pathway in a variety of cell types. However, the molecular basis of this suppression has not been clarified. Spred/Sprouty family proteins are also negative regulators of the ERK pathway by interacting with Raf-1. The Spred/Sprouty family proteins contain a cysteine-rich (CR) domain at the C-terminus, which is thought to be palmitoylated like Cav-1 and necessary for membrane anchoring. In this study, we demonstrated that Spred-1 localized in cholesterol-rich membrane raft/caveola fractions and interacted with Cav-1. To clarify the biological effect of Cav-1/Spred-1 interaction, we used hematopoietic cells that lacked expression of caveolins but expressed Spred-1. Forced expression of Cav-1 suppressed SCF- and IL-3-induced proliferation and ERK activation. Furthermore, forced expression of exogenous Spred-1 in Cav-1-expressing cells further suppressed proliferation and ERK activation. These data suggest that Spred-1 inhibits ERK activation in collaboration with Cav-1. © Blackwell Publishing Limited.

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Exacerbation of experimental allergic asthma by augmented Th2 responses in WSX-1-deficient mice

Miyazaki Yoshiyuki, Inoue Hiromasa, Matsumura Mikiko, Matsumoto Koichiro, Nakano Takako, Tsuda Miyuki, Hamano Shinjiro, Yoshimura Akihiko, Yoshida Hiroki

Journal of Immunology 175 ( 4 ) 2401 - 2407 2005.08

ISSN 0022-1767

WSX-1 (IL-27R) is a class I cytokine receptor with homology to gp130 and IL-12 receptors and is typically expressed on CD4⁺ T lymphocytes. Although previous reports have clarified that IL-27/WSX-1 signaling plays critical roles in both Th1 differentiation and attenuation of cell activation and proinflammatory cytokine production during some bacterial or protozoan infections, little is known about the importance of WSX-1 in cytokine-mediated diseases of allergic origin. To this aim, we took advantage of WSX-1-deficient (WSX-1^-/-) mice and induced experimental asthma, in which Th2 cytokines are central modulators of the pathology. OVA-challenged WSX-1 ^-/- mice showed marked enhancement of airway responsiveness with goblet cell hyperplasia, pulmonary eosinophil infiltration, and increased serum IgE levels compared with wild-type mice. Production of Th2 cytokines, which are largely responsible for the pathogenesis of asthma, was augmented in the lung or in the culture supernatants of peribronchial lymph node CD4⁺ T cells from WSX-1^-/- mice compared with those from wild-type mice. Surprisingly, IFN-γ production was also enhanced in WSX-1^-/- mice, albeit at a low concentration. The cytokine overproduction, thus, seems independent from the Th1-promoting property of WSX-1. These results demonstrated that IL-27/WSX-1 also plays an important role in the down-regulation of airway hyper-reactivity and lung inflammation during the development of allergic asthma through its suppressive effect on cytokine production. Copyright © 2005 by The American Association of Immunologists, Inc.

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