Papers - Yoshimura, Akihiko

Legius syndrome in fourteen families

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

Human Mutation 32 ( 1 )  2011.01

ISSN  1059-7794

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

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[Suppression of leptin and insulin signaling by SOCS3].

Yoshimura Akihiko

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

ISSN  0047-1852

Prostaglandin E2 and SOCS1 have a role in intestinal immune tolerance

Chinen Takatoshi, Komai Kyoko, Muto Go, Morita Rimpei, Inoue Naoko, Yoshida Hideyuki, Sekiya Takashi, Yoshida Ryoko, Nakamura Kazuhiko, Takayanagi Ryoichi, Yoshimura Akihiko

Nature Communications 2 ( 1 )  2011

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<p>Interleukin 10 (IL-10) and regulatory T cells (Tregs) maintain tolerance to intestinal microorganisms. However, Il10^-/- Rag2^-/- mice, which lack IL-10 and Tregs, remain healthy, suggesting the existence of other mechanisms of tolerance. Here, we identify suppressor of cytokine signalling 1 (SOCS1) as an essential mediator of immune tolerance in the intestine. Socs1^-/- Rag2^-/- mice develop severe colitis, which can be prevented by the reduction of microbiota and the transfer of IL-10-sufficient Tregs. Additionally, we find an essential role for prostaglandin E2 (PGE2) in the maintenance of tolerance within the intestine in the absence of Tregs. Socs1^-/- dendritic cells are resistant to PGE2-mediated immunosuppression because of dysregulated cytokine signalling. Thus, we propose that SOCS1 and PGE2, potentially interacting together, act as an alternative intestinal tolerance mechanism distinct from IL-10 and Tregs. © 2011 Macmillan Publishers Limited. All rights reserved.</p>

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The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4⁺ T cells

Sekiya Takashi, Kashiwagi Ikkou, Inoue Naoko, Morita Rimpei, Hori Shohei, Waldmann Herman, Rudensky Alexander Y., Ichinose Hiroshi, Metzger Daniel, Chambon Pierre, Yoshimura Akihiko

Nature Communications 2 ( 1 )  2011

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<p>Regulatory T cells (Tregs) have a central role in maintaining immune homoeostasis through various mechanisms. Although the Forkhead transcription factor Foxp3 defines the Treg cell lineage and functions, the molecular mechanisms of Foxp3 induction and maintenance remain elusive. Here we show that Foxp3 is one of the direct targets of Nr4a2. Nr4a2 binds to regulatory regions of Foxp3, where it mediates permissive histone modifications. Ectopic expression of Nr4a2 imparts Treg-like suppressive activity to naïve CD4⁺ T cells by inducing Foxp3 and by repressing cytokine production, including interferon-γ and interleukin-2. Deletion of Nr4a2 in T cells attenuates induction of Tregs and causes aberrant induction of Th1, leading to the exacerbation of colitis. Nr4a2-deficeint Tregs are prone to lose Foxp3 expression and have attenuated suppressive ability both in vitro and in vivo. Thus, Nr4a2 has the ability to maintain T-cell homoeostasis by regulating induction, maintenance and suppressor functions of Tregs, and by repression of aberrant Th1 induction. © 2011 Macmillan Publishers Limited. All rights reserved.</p>

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TGF-β function in immune suppression.

Yoshimura Akihiko, Muto G.

Current topics in microbiology and immunology 350   127 - 147 2011

ISSN  0070-217X

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<p>Transforming growth factor-β (TGF-β) has been shown to play an essential role in establishing immunological tolerance, yet recent studies have revealed the pro-inflammatory roles of TGF-β in inflammatory responses. TGF-β induces Foxp3-positive regulatory T cells (iTregs), while in the presence of IL-6, it induces pathogenic IL-17 producing Th17 cells. TGF-β inhibits the proliferation of T cells as well as cytokine production via Foxp3-dependent and independent mechanisms. On the one hand, little is known about molecular mechanisms involved in immune suppression via TGF-β; however, recent studies suggest that Smad2 as well as Smad3 play essential roles in Foxp3 induction and cytokine suppression, whereas Th17 differentiation is promoted via the Smad-independent pathway. Mutual suppression of signaling between TGF-β and inflammatory cytokines has been shown to be necessary for the balance of immunity and tolerance.</p>

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Aberrant IL-4 production by SOCS3-over-expressing T cells during infection with Leishmania major exacerbates disease manifestations

Nakaya Mako, Hamano Shinjiro, Kawasumi Miyuri, Yoshida Hiroki, Yoshimura Akihiko, Kobayashi Takashi

International Immunology 23 ( 3 ) 195 - 202 2011

ISSN  0953-8178

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<p>Suppressor of cytokine signaling (SOCS) 3 is a major negative feedback regulator of signal transducer and activator of transcription 3-activating cytokines. Studies using T-cell-specific SOCS3-deficient mice indicate that the absence of SOCS3 in T cells results in exacerbation of disease progression after infection by Leishmania major due to skewing of the T_h3 cell phenotype accompanied by hyper-production of IL-10 and transforming growth factor β (TGF-β). Here we show that transgenic mice over-expressing the SOCS3 gene in T cells (Lck-SOCS3 Tg mice) are also susceptible to infection by L. major. Forced expression of SOCS3 in T cells did not affect the production of the anti-inflammatory cytokines IL-10 and TGF-β or that of the protective T_h1 type cytokine IFN-γ, which is required for parasite clearance. CD⁴1 T cells isolated from infected-Lck-SOCS3 Tg mice produced much higher levels of IL-4 when they were restimulated with L. major antigen in vitro. Exacerbation of disease progression in Lck-SOCS3 Tg mice was completely reversed by administration of a neutralizing antibody against IL-4. These data suggest that tight regulation of SOCS3 expression in T_h cells is crucial for disease control during infection by L. major. © The Japanese Society for Immunology. 2011. All rights reserved.</p>

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SOCS1 regulates type I/type II NKT cell balance by regulating IFNγ signaling

Hashimoto Masayuki, Hiwatashi Kiyokazu, Ichiyama Kenji, Morita Rimpei, Sekiya Takashi, Kimura Akihiro, Sugiyama Yuki, Sibata Toshikatsu, Kuroda Kazumichi, Takahashi Reiko, Yoshimura Akihiko

International Immunology 23 ( 3 ) 165 - 176 2011

ISSN  0953-8178

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<p>Suppressor of cytokine signaling-1 (SOCS1) has been shown to be an essential negative regulator of cytokine responses, including those of IFNγ, IL-2, IL-4 and IL-7. SOCS1 deficiency resulted in hyperactivation not only of T cells in general but also of NKT cells specifically. Consistent with previous reports, T- and NKT-cell-specific deletion of Socs1 in mice resulted in enhanced sensitivity to ConA-induced hepatitis. Compared with wild-type (WT) NKT cells, SOCS1-deficient NKT cells produced larger quantities of IFNγg in response to ConA and proliferated faster in response to IL-2 and IL-15. To our surprise, however, SOCS1-deficient NKT cells did not respond to the synthetic glycolipid ligand alpha-galactosylceramide (α-GalCer), though they did respond to sulfatide. α-GalCer-CD1d-tetramer-positive type I NKT [invariant NKT (iNKT)] cells were marginally detected in the periphery of SOCS1-conditional knockout (cKO) mice, suggesting that most of the SOCS1-deficient NKT cells at the periphery were type II NKT cells. Consistently, invariant Vα14 expression was much lower in SOCS1-deficient NKT cells than in WT NKT cells, indicating that iNKT cell homeostasis was abnormal in SOCS1-cKO mice. This reduction in iNKT cells was not observed in mice of an IFNγ-deficient background. These results suggest that SOCS1 is an important regulator of the balance between type I and type II NKT cells at the periphery. © The Japanese Society for Immunology. 2011. All rights reserved.</p>

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Prostaglandin E2 and SOCS1 have a role in intestinal immune tolerance

Chinen Takatoshi, Komai Kyoko, Muto Go, Morita Rimpei, Inoue Naoko, Yoshida Hideyuki, Sekiya Takashi, Yoshida Ryoko, Nakamura Kazuhiko, Takayanagi Ryoichi, Yoshimura Akihiko

Nature Communications 2 ( 1 )  2011

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<p>Interleukin 10 (IL-10) and regulatory T cells (Tregs) maintain tolerance to intestinal microorganisms. However, Il10^-/- Rag2^-/- mice, which lack IL-10 and Tregs, remain healthy, suggesting the existence of other mechanisms of tolerance. Here, we identify suppressor of cytokine signalling 1 (SOCS1) as an essential mediator of immune tolerance in the intestine. Socs1^-/- Rag2^-/- mice develop severe colitis, which can be prevented by the reduction of microbiota and the transfer of IL-10-sufficient Tregs. Additionally, we find an essential role for prostaglandin E2 (PGE2) in the maintenance of tolerance within the intestine in the absence of Tregs. Socs1^-/- dendritic cells are resistant to PGE2-mediated immunosuppression because of dysregulated cytokine signalling. Thus, we propose that SOCS1 and PGE2, potentially interacting together, act as an alternative intestinal tolerance mechanism distinct from IL-10 and Tregs. © 2011 Macmillan Publishers Limited. All rights reserved.</p>

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The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4⁺ T cells

Sekiya Takashi, Kashiwagi Ikkou, Inoue Naoko, Morita Rimpei, Hori Shohei, Waldmann Herman, Rudensky Alexander Y., Ichinose Hiroshi, Metzger Daniel, Chambon Pierre, Yoshimura Akihiko

Nature Communications 2 ( 1 )  2011

　View Summary

<p>Regulatory T cells (Tregs) have a central role in maintaining immune homoeostasis through various mechanisms. Although the Forkhead transcription factor Foxp3 defines the Treg cell lineage and functions, the molecular mechanisms of Foxp3 induction and maintenance remain elusive. Here we show that Foxp3 is one of the direct targets of Nr4a2. Nr4a2 binds to regulatory regions of Foxp3, where it mediates permissive histone modifications. Ectopic expression of Nr4a2 imparts Treg-like suppressive activity to naïve CD4⁺ T cells by inducing Foxp3 and by repressing cytokine production, including interferon-γ and interleukin-2. Deletion of Nr4a2 in T cells attenuates induction of Tregs and causes aberrant induction of Th1, leading to the exacerbation of colitis. Nr4a2-deficeint Tregs are prone to lose Foxp3 expression and have attenuated suppressive ability both in vitro and in vivo. Thus, Nr4a2 has the ability to maintain T-cell homoeostasis by regulating induction, maintenance and suppressor functions of Tregs, and by repression of aberrant Th1 induction. © 2011 Macmillan Publishers Limited. All rights reserved.</p>

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TGF-β function in immune suppression.

Yoshimura Akihiko, Muto G.

Current topics in microbiology and immunology 350   127 - 147 2011

ISSN  0070-217X

　View Summary

<p>Transforming growth factor-β (TGF-β) has been shown to play an essential role in establishing immunological tolerance, yet recent studies have revealed the pro-inflammatory roles of TGF-β in inflammatory responses. TGF-β induces Foxp3-positive regulatory T cells (iTregs), while in the presence of IL-6, it induces pathogenic IL-17 producing Th17 cells. TGF-β inhibits the proliferation of T cells as well as cytokine production via Foxp3-dependent and independent mechanisms. On the one hand, little is known about molecular mechanisms involved in immune suppression via TGF-β; however, recent studies suggest that Smad2 as well as Smad3 play essential roles in Foxp3 induction and cytokine suppression, whereas Th17 differentiation is promoted via the Smad-independent pathway. Mutual suppression of signaling between TGF-β and inflammatory cytokines has been shown to be necessary for the balance of immunity and tolerance.</p>

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Aberrant IL-4 production by SOCS3-over-expressing T cells during infection with Leishmania major exacerbates disease manifestations

Nakaya Mako, Hamano Shinjiro, Kawasumi Miyuri, Yoshida Hiroki, Yoshimura Akihiko, Kobayashi Takashi

International Immunology 23 ( 3 ) 195 - 202 2011

ISSN  0953-8178

　View Summary

<p>Suppressor of cytokine signaling (SOCS) 3 is a major negative feedback regulator of signal transducer and activator of transcription 3-activating cytokines. Studies using T-cell-specific SOCS3-deficient mice indicate that the absence of SOCS3 in T cells results in exacerbation of disease progression after infection by Leishmania major due to skewing of the T_h3 cell phenotype accompanied by hyper-production of IL-10 and transforming growth factor β (TGF-β). Here we show that transgenic mice over-expressing the SOCS3 gene in T cells (Lck-SOCS3 Tg mice) are also susceptible to infection by L. major. Forced expression of SOCS3 in T cells did not affect the production of the anti-inflammatory cytokines IL-10 and TGF-β or that of the protective T_h1 type cytokine IFN-γ, which is required for parasite clearance. CD⁴1 T cells isolated from infected-Lck-SOCS3 Tg mice produced much higher levels of IL-4 when they were restimulated with L. major antigen in vitro. Exacerbation of disease progression in Lck-SOCS3 Tg mice was completely reversed by administration of a neutralizing antibody against IL-4. These data suggest that tight regulation of SOCS3 expression in T_h cells is crucial for disease control during infection by L. major. © The Japanese Society for Immunology. 2011. All rights reserved.</p>

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SOCS1 regulates type I/type II NKT cell balance by regulating IFNγ signaling

Hashimoto Masayuki, Hiwatashi Kiyokazu, Ichiyama Kenji, Morita Rimpei, Sekiya Takashi, Kimura Akihiro, Sugiyama Yuki, Sibata Toshikatsu, Kuroda Kazumichi, Takahashi Reiko, Yoshimura Akihiko

International Immunology 23 ( 3 ) 165 - 176 2011

ISSN  0953-8178

　View Summary

<p>Suppressor of cytokine signaling-1 (SOCS1) has been shown to be an essential negative regulator of cytokine responses, including those of IFNγ, IL-2, IL-4 and IL-7. SOCS1 deficiency resulted in hyperactivation not only of T cells in general but also of NKT cells specifically. Consistent with previous reports, T- and NKT-cell-specific deletion of Socs1 in mice resulted in enhanced sensitivity to ConA-induced hepatitis. Compared with wild-type (WT) NKT cells, SOCS1-deficient NKT cells produced larger quantities of IFNγg in response to ConA and proliferated faster in response to IL-2 and IL-15. To our surprise, however, SOCS1-deficient NKT cells did not respond to the synthetic glycolipid ligand alpha-galactosylceramide (α-GalCer), though they did respond to sulfatide. α-GalCer-CD1d-tetramer-positive type I NKT [invariant NKT (iNKT)] cells were marginally detected in the periphery of SOCS1-conditional knockout (cKO) mice, suggesting that most of the SOCS1-deficient NKT cells at the periphery were type II NKT cells. Consistently, invariant Vα14 expression was much lower in SOCS1-deficient NKT cells than in WT NKT cells, indicating that iNKT cell homeostasis was abnormal in SOCS1-cKO mice. This reduction in iNKT cells was not observed in mice of an IFNγ-deficient background. These results suggest that SOCS1 is an important regulator of the balance between type I and type II NKT cells at the periphery. © The Japanese Society for Immunology. 2011. All rights reserved.</p>

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Interactions of STAP-2 with Brk and STAT3 participate in cell growth of human breast cancer cells

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

Journal of Biological Chemistry 285 ( 49 ) 38093 - 38103 2010.12

ISSN  0021-9258

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<p>STAP-2 (signal transducing adaptor protein-2) is a recently identified adaptor protein that contains pleckstrin homology (PH) and Src homology 2-like domains, as well as a STAT3-binding motif in its C-terminal region. STAP-2 is also a substrate of breast tumor kinase (Brk). In breast cancers, Brk expression is deregulated and promotes STAT3-dependent cell proliferation. In the present study, manipulated STAP-2 expression demonstrated essential roles of STAP-2 in Brk-mediated STAT3 activation. STAP-2 interacts with both Brk and STAT3. In addition, small interfering RNA-mediated reduction of endogenous STAP-2 expression strongly decreased Brk-mediated STAT3 activation in T47D breast cancer cells. The PH domain of STAP-2 is involved in multiple steps: the binding between Brk and STAP-2, the activation and tyrosine phosphorylation of STAT3, and the activation of Brk. Notably, a STAP-2 PH-Brk fusion protein exhibited robust kinase activity and increased activation and tyrosine phosphorylation of STAT3. Finally, STAP-2 knockdown in T47D cells induced a significant decrease of proliferation, as strong as that of Brk or STAT3 knockdown. Taken together, our findings are likely to inform the development of a novel therapeutic strategy, as well as the determination of novel prognostic values, in breast carcinomas. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.</p>

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Interactions of STAP-2 with Brk and STAT3 participate in cell growth of human breast cancer cells

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

Journal of Biological Chemistry 285 ( 49 ) 38093 - 38103 2010.12

ISSN  0021-9258

　View Summary

<p>STAP-2 (signal transducing adaptor protein-2) is a recently identified adaptor protein that contains pleckstrin homology (PH) and Src homology 2-like domains, as well as a STAT3-binding motif in its C-terminal region. STAP-2 is also a substrate of breast tumor kinase (Brk). In breast cancers, Brk expression is deregulated and promotes STAT3-dependent cell proliferation. In the present study, manipulated STAP-2 expression demonstrated essential roles of STAP-2 in Brk-mediated STAT3 activation. STAP-2 interacts with both Brk and STAT3. In addition, small interfering RNA-mediated reduction of endogenous STAP-2 expression strongly decreased Brk-mediated STAT3 activation in T47D breast cancer cells. The PH domain of STAP-2 is involved in multiple steps: the binding between Brk and STAP-2, the activation and tyrosine phosphorylation of STAT3, and the activation of Brk. Notably, a STAP-2 PH-Brk fusion protein exhibited robust kinase activity and increased activation and tyrosine phosphorylation of STAT3. Finally, STAP-2 knockdown in T47D cells induced a significant decrease of proliferation, as strong as that of Brk or STAT3 knockdown. Taken together, our findings are likely to inform the development of a novel therapeutic strategy, as well as the determination of novel prognostic values, in breast carcinomas. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.</p>

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Development of experimental cerebral malaria is independent of IL-23 and IL-17

Ishida Hidekazu, Matsuzaki-Moriya Chikako, Imai Takashi, Yanagisawa Kunio, Nojima Yoshihisa, Suzue Kazutomo, Hirai Makoto, Iwakura Yoichiro, Yoshimura Akihiko, Hamano Shinjiro, Shimokawa Chikako, Hisaeda Hajime

Biochemical and Biophysical Research Communications 402 ( 4 ) 790 - 795 2010.11

ISSN  0006-291X

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<p>Cerebral malaria (CM) is the most severe complication of Plasmodium infection. Although inappropriate immune responses to Plasmodium falciparum are reported as the major causes of CM, the precise mechanisms for development remain unclear. IL-23 and IL-17 have critical roles in the onset of autoimmunity and inflammatory diseases triggered by microbial infections. Thus, we investigated the influence of IL-23 and IL-17 on experimental CM (ECM) using Plasmodium berghei ANKA infection of C57BL/6 mice. Both IL-23 deficient mice and wild-type (WT) mice developed ECM. IL-17 deficient mice also developed ECM, while IL-17 producing cells other than CD4 ⁺ T cells (Th17) were increased in WT mice that developed ECM. In conclusion, this study showed that IL-23 and IL-17 are not involved in ECM development. © 2010 Elsevier Inc.</p>

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Suppressor of cytokine signaling 3 inhibits LPS-induced IL-6 expression in osteoblasts by suppressing CCAAT/enhancer-binding protein

Yan Chunguang, Cao Jay, Wu Min, Zhang Wei, Jiang Tao, Yoshimura Aihiko, Gao Hongwei

Journal of Biological Chemistry 285 ( 48 ) 37227 - 37239 2010.11

ISSN  0021-9258

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<p>Suppressor of cytokine signaling 3 (SOCS3) is an important intracellular protein that inhibits cytokine signaling in numerous cell types and has been implicated in several inflammatory diseases. However, the expression and function of SOCS3 in osteoblasts are not known. In this study, we demonstrated that SOCS3 expression was transiently induced by LPS in osteoblasts, and apparently contributed to the inhibition of IL-6 induction by LPS treatment. We found that tyrosine 204 of the SOCS box, the SH2 domain, and the N-terminal kinase inhibitory region (KIR) of SOCS3 were all involved in its IL-6 inhibition. Furthermore, we demonstrated that CCAAT/enhancerbinding protein (C/EBP) β was activated by LPS (increased DNA binding activity), and played a key role in LPS-induced IL-6 expression in osteoblasts. We further provided the evidence that SOCS3 functioned as a negative regulator for LPS response in osteoblasts by suppressing C/EBPβ DNA binding activity. In addition, tyrosine 204 of the SOCS box, the SH2 domain, and the N-terminal kinase inhibitory region (KIR) of SOCS3 were all required for its C/EBPβ inhibition. These findings suggest that SOCS3 by interfering with C/EBPβ activation may have an important regulatory role during bone-associated inflammatory responses.</p>

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Development of experimental cerebral malaria is independent of IL-23 and IL-17

Ishida Hidekazu, Matsuzaki-Moriya Chikako, Imai Takashi, Yanagisawa Kunio, Nojima Yoshihisa, Suzue Kazutomo, Hirai Makoto, Iwakura Yoichiro, Yoshimura Akihiko, Hamano Shinjiro, Shimokawa Chikako, Hisaeda Hajime

Biochemical and Biophysical Research Communications 402 ( 4 ) 790 - 795 2010.11

ISSN  0006-291X

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<p>Cerebral malaria (CM) is the most severe complication of Plasmodium infection. Although inappropriate immune responses to Plasmodium falciparum are reported as the major causes of CM, the precise mechanisms for development remain unclear. IL-23 and IL-17 have critical roles in the onset of autoimmunity and inflammatory diseases triggered by microbial infections. Thus, we investigated the influence of IL-23 and IL-17 on experimental CM (ECM) using Plasmodium berghei ANKA infection of C57BL/6 mice. Both IL-23 deficient mice and wild-type (WT) mice developed ECM. IL-17 deficient mice also developed ECM, while IL-17 producing cells other than CD4 ⁺ T cells (Th17) were increased in WT mice that developed ECM. In conclusion, this study showed that IL-23 and IL-17 are not involved in ECM development. © 2010 Elsevier Inc.</p>

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Suppressor of cytokine signaling 3 inhibits LPS-induced IL-6 expression in osteoblasts by suppressing CCAAT/enhancer-binding protein

Yan Chunguang, Cao Jay, Wu Min, Zhang Wei, Jiang Tao, Yoshimura Aihiko, Gao Hongwei

Journal of Biological Chemistry 285 ( 48 ) 37227 - 37239 2010.11

ISSN  0021-9258

　View Summary

<p>Suppressor of cytokine signaling 3 (SOCS3) is an important intracellular protein that inhibits cytokine signaling in numerous cell types and has been implicated in several inflammatory diseases. However, the expression and function of SOCS3 in osteoblasts are not known. In this study, we demonstrated that SOCS3 expression was transiently induced by LPS in osteoblasts, and apparently contributed to the inhibition of IL-6 induction by LPS treatment. We found that tyrosine 204 of the SOCS box, the SH2 domain, and the N-terminal kinase inhibitory region (KIR) of SOCS3 were all involved in its IL-6 inhibition. Furthermore, we demonstrated that CCAAT/enhancerbinding protein (C/EBP) β was activated by LPS (increased DNA binding activity), and played a key role in LPS-induced IL-6 expression in osteoblasts. We further provided the evidence that SOCS3 functioned as a negative regulator for LPS response in osteoblasts by suppressing C/EBPβ DNA binding activity. In addition, tyrosine 204 of the SOCS box, the SH2 domain, and the N-terminal kinase inhibitory region (KIR) of SOCS3 were all required for its C/EBPβ inhibition. These findings suggest that SOCS3 by interfering with C/EBPβ activation may have an important regulatory role during bone-associated inflammatory responses.</p>

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Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model

Konoeda Fumie, Shichita Takashi, Yoshida Hideyuki, Sugiyama Yuki, Muto Go, Hasegawa Eiichi, Morita Rinpei, Suzuki Norihiro, Yoshimura Akihiko

Biochemical and Biophysical Research Communications 402 ( 3 ) 500 - 506 2010.11

ISSN  0006-291X

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<p>Recently, T cell cytokines such as IL-17 and IFN-γ have been shown to play important roles in the progression of brain injury induced by ischemia. We have shown that IL-23 from infiltrated macrophages activates γδT cells, thereby inducing IL-17 from these cells. However, deletion of the IL-23 gene in mice showed a more dramatic protective effect against brain ischemia reperfusion (I/R) model than γδT cell depletion did, suggesting that IL-23 plays some other pivotal role in brain injury in addition to its role in IL-17 induction. To develop therapeutic methods based on these findings, we examined the effect of the JAK kinase inhibitor CP-690550 and an anti-IL12/23 monoclonal antibody on an I/R model. CP-690550 efficiently inhibited IL-17 production from memory T cells in vitro and partly suppressed infarct volume increase after I/R. Anti-p40 antibody, which blocks both IL-12 and IL-23, efficiently suppressed I/R injury and improved recovery of neurological deficits. The number of IL-17-producing cells was decreased by anti-p40 antibody treatment. Thus the JAK inhibitor and anti-p40 antibody, both of which have already been under trial for the treatment of several human inflammatory diseases, appear to be promising therapeutic agents for the amelioration of stroke. © 2010 Elsevier Inc.</p>

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Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model

Konoeda Fumie, Shichita Takashi, Yoshida Hideyuki, Sugiyama Yuki, Muto Go, Hasegawa Eiichi, Morita Rinpei, Suzuki Norihiro, Yoshimura Akihiko

Biochemical and Biophysical Research Communications 402 ( 3 ) 500 - 506 2010.11

ISSN  0006-291X

　View Summary

<p>Recently, T cell cytokines such as IL-17 and IFN-γ have been shown to play important roles in the progression of brain injury induced by ischemia. We have shown that IL-23 from infiltrated macrophages activates γδT cells, thereby inducing IL-17 from these cells. However, deletion of the IL-23 gene in mice showed a more dramatic protective effect against brain ischemia reperfusion (I/R) model than γδT cell depletion did, suggesting that IL-23 plays some other pivotal role in brain injury in addition to its role in IL-17 induction. To develop therapeutic methods based on these findings, we examined the effect of the JAK kinase inhibitor CP-690550 and an anti-IL12/23 monoclonal antibody on an I/R model. CP-690550 efficiently inhibited IL-17 production from memory T cells in vitro and partly suppressed infarct volume increase after I/R. Anti-p40 antibody, which blocks both IL-12 and IL-23, efficiently suppressed I/R injury and improved recovery of neurological deficits. The number of IL-17-producing cells was decreased by anti-p40 antibody treatment. Thus the JAK inhibitor and anti-p40 antibody, both of which have already been under trial for the treatment of several human inflammatory diseases, appear to be promising therapeutic agents for the amelioration of stroke. © 2010 Elsevier Inc.</p>

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