論文 - 吉村　昭彦

Histone 3 lysine 9 (H3K9) methyltransferase recruitment to the interleukin-2 (IL-2) promoter is a mechanism of suppression of IL-2 transcription by the transforming growth factor-β-smad pathway

Wakabayashi Yu, Tamiya Taiga, Takada Ichiro, Fukaya Tomohiro, Sugiyama Yuki, Inoue Naoko, Kimura Akihiro, Morita Rimpei, Kashiwagi Ikko, Takimoto Tomohito, Nomura Masatoshi, Yoshimura Akihiko

Journal of Biological Chemistry 286 （ 41 ） 35456 - 35465 2011年10月

ISSN  0021-9258

　概要を見る

<p>Suppression of IL-2βproduction from T cells is an important process for the immune regulation by TGF-β. However, the mechanism by which this suppression occurs remains to be established. Here, we demonstrate that Smad2 and Smad3, two major TGF-β-downstream transcription factors, are redundantly essential for TGF-β-mediated suppression of IL-2 production in CD4 ⁺ T cells using Smad2- and Smad3-deficient T cells. Both Smad2 and Smad3 were recruited into the proximal region of the IL-2 promoter in response to TGF-β. We then investigated the histone methylation status of the IL-2 promoter. Although both histone H3 lysine 9 (H3K9) and H3K27 trimethylation have been implicated in gene silencing, only H3K9 trimethylation was increased in the proximal region of the IL-2 promoter in a Smad2/3-dependent manner, whereas H3K27 trimethylation was not. The H3K9 methyltransferases Setdb1 and Suv39h1 bound to Smad3 and suppressed IL-2 promoter activity in collaboration with Smad3. Overexpression of Suv39h1 in 68-41 T cells strongly inhibited IL-2 production in response to T cell receptor stimulation irrespective of the presence or absence of TGF-β, whereas Setdb1 overexpression only slightly suppressed IL-2 production. Silencing of Suv39h1 by shRNA reverted the suppressive effect of TGF-β on IL-2 production. Furthermore, TGF-β induced Suv39h1 recruitment to the proximal region of the IL-2 promoter in wild type primary T cells; however, this was not observed in Smad2 ^-/-Smad3 ^+/- T cells. Thus, we propose that Smads recruit H3K9 methyltransferases Suv39h1 to the IL-2 promoter, thereby inducing suppressive histone methylation and inhibiting T cell receptor-mediated IL-2 transcription. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.</p>

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Histone 3 lysine 9 (H3K9) methyltransferase recruitment to the interleukin-2 (IL-2) promoter is a mechanism of suppression of IL-2 transcription by the transforming growth factor-β-smad pathway

Wakabayashi Yu, Tamiya Taiga, Takada Ichiro, Fukaya Tomohiro, Sugiyama Yuki, Inoue Naoko, Kimura Akihiro, Morita Rimpei, Kashiwagi Ikko, Takimoto Tomohito, Nomura Masatoshi, Yoshimura Akihiko

Journal of Biological Chemistry 286 （ 41 ） 35456 - 35465 2011年10月

ISSN  0021-9258

　概要を見る

<p>Suppression of IL-2βproduction from T cells is an important process for the immune regulation by TGF-β. However, the mechanism by which this suppression occurs remains to be established. Here, we demonstrate that Smad2 and Smad3, two major TGF-β-downstream transcription factors, are redundantly essential for TGF-β-mediated suppression of IL-2 production in CD4 ⁺ T cells using Smad2- and Smad3-deficient T cells. Both Smad2 and Smad3 were recruited into the proximal region of the IL-2 promoter in response to TGF-β. We then investigated the histone methylation status of the IL-2 promoter. Although both histone H3 lysine 9 (H3K9) and H3K27 trimethylation have been implicated in gene silencing, only H3K9 trimethylation was increased in the proximal region of the IL-2 promoter in a Smad2/3-dependent manner, whereas H3K27 trimethylation was not. The H3K9 methyltransferases Setdb1 and Suv39h1 bound to Smad3 and suppressed IL-2 promoter activity in collaboration with Smad3. Overexpression of Suv39h1 in 68-41 T cells strongly inhibited IL-2 production in response to T cell receptor stimulation irrespective of the presence or absence of TGF-β, whereas Setdb1 overexpression only slightly suppressed IL-2 production. Silencing of Suv39h1 by shRNA reverted the suppressive effect of TGF-β on IL-2 production. Furthermore, TGF-β induced Suv39h1 recruitment to the proximal region of the IL-2 promoter in wild type primary T cells; however, this was not observed in Smad2 ^-/-Smad3 ^+/- T cells. Thus, we propose that Smads recruit H3K9 methyltransferases Suv39h1 to the IL-2 promoter, thereby inducing suppressive histone methylation and inhibiting T cell receptor-mediated IL-2 transcription. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.</p>

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Suppression of SOCS3 in macrophages prevents cancer metastasis by modifying macrophage phase and MCP2/CCL8 induction

Hiwatashi Kiyokazu, Tamiya Taiga, Hasegawa Eiichi, Fukaya Tomohiro, Hashimoto Masayuki, Kakoi Kyosuke, Kashiwagi Ikko, Kimura Akihiro, Inoue Naoko, Morita Rimpei, Yasukawa Hideo, Yoshimura Akihiko

Cancer Letters 308 （ 2 ） 172 - 180 2011年09月

ISSN  0304-3835

　概要を見る

<p>Inflammation has been demonstrated to play important roles in tumorigenesis, tumor progression, and metastasis. STAT3 has been shown to be frequently activated in a variety of human cancer cells and STAT3 signaling promotes the growth and survival of tumor cells. However, the role of STAT3 of myeloid cells associated with tumors is currently unknown. Suppressor of cytokine signaling-3 (SOCS3) has been shown to be a negative regulator of STAT3. In this study, we used macrophage specific SOCS3 conditional knockout (cKO) mice to investigate the effect of the hyperactivation of STAT3 in macrophages on tumor development and metastasis. In a subcutaneous transplantation model of B16F10 melanoma cells, although tumor sizes were not significantly different, SOCS3-cKO mice survived longer than wild-type (WT) mice did. SOCS3-cKO mice exhibited fewer lung and liver metastatic tumor nodules than WT mice when B16F10 was challenged intravenously. SOCS3^-/- macrophages stimulated with tumor lysates in vitro exhibited prolonged STAT3 phosphorylation and produced less amount of TNFα and IL-6, and higher amount of MCP2/CCL8 than WT macrophages. MCP/CCL8 was induced via STAT3 and exhibited anti-tumor metastatic effect in WT mice. These data suggest that hyperactivation of STAT3 in myeloid cells simultaneously exerted an anti-inflammatory as well as anti-tumor effects. Thus, the targeted inhibition of SOCS3 activity in macrophages may be therapeutic for the suppression of tumor metastasis. © 2011 Elsevier Ireland Ltd.</p>

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Suppression of SOCS3 in macrophages prevents cancer metastasis by modifying macrophage phase and MCP2/CCL8 induction

Hiwatashi Kiyokazu, Tamiya Taiga, Hasegawa Eiichi, Fukaya Tomohiro, Hashimoto Masayuki, Kakoi Kyosuke, Kashiwagi Ikko, Kimura Akihiro, Inoue Naoko, Morita Rimpei, Yasukawa Hideo, Yoshimura Akihiko

Cancer Letters 308 （ 2 ） 172 - 180 2011年09月

ISSN  0304-3835

　概要を見る

<p>Inflammation has been demonstrated to play important roles in tumorigenesis, tumor progression, and metastasis. STAT3 has been shown to be frequently activated in a variety of human cancer cells and STAT3 signaling promotes the growth and survival of tumor cells. However, the role of STAT3 of myeloid cells associated with tumors is currently unknown. Suppressor of cytokine signaling-3 (SOCS3) has been shown to be a negative regulator of STAT3. In this study, we used macrophage specific SOCS3 conditional knockout (cKO) mice to investigate the effect of the hyperactivation of STAT3 in macrophages on tumor development and metastasis. In a subcutaneous transplantation model of B16F10 melanoma cells, although tumor sizes were not significantly different, SOCS3-cKO mice survived longer than wild-type (WT) mice did. SOCS3-cKO mice exhibited fewer lung and liver metastatic tumor nodules than WT mice when B16F10 was challenged intravenously. SOCS3^-/- macrophages stimulated with tumor lysates in vitro exhibited prolonged STAT3 phosphorylation and produced less amount of TNFα and IL-6, and higher amount of MCP2/CCL8 than WT macrophages. MCP/CCL8 was induced via STAT3 and exhibited anti-tumor metastatic effect in WT mice. These data suggest that hyperactivation of STAT3 in myeloid cells simultaneously exerted an anti-inflammatory as well as anti-tumor effects. Thus, the targeted inhibition of SOCS3 activity in macrophages may be therapeutic for the suppression of tumor metastasis. © 2011 Elsevier Ireland Ltd.</p>

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SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production

Takahashi Reiko, Nishimoto Shuhei, Muto Go, Sekiya Takashi, Tamiya Taiga, Kimura Akihiro, Morita Rimpei, Asakawa Mayako, Chinen Takatoshi, Yoshimura Akihiko

Journal of Experimental Medicine 208 （ 10 ） 2055 - 2067 2011年09月

ISSN  0022-1007

　概要を見る

<p>Regulatory T cells (T_reg cells) maintain immune homeostasis by limiting inflammatory responses. SOCS1 (suppressor of cytokine signaling 1), a negative regulator of cytokine signaling, is necessary for the suppressor functions of T_reg cells in vivo, yet detailed mechanisms remain to be clarified. We found that Socs1^-/- Treg cells produced high levels of IFN-γ and rapidly lost Foxp3 when transferred into Rag2^-/- mice or cultured in vitro, even though the CNS2 (conserved noncoding DNA sequence 2) in the Foxp3 enhancer region was fully demethylated. Socs1^-/- T_reg cells showed hyperactivation of STAT1 and STAT3. Because Foxp3 expression was stable and STAT1 activation was at normal levels in Ifnγ^-/-Socs1^-/- T_reg cells, the restriction of IFN-γ-STAT1 signaling by SOCS1 is suggested to be necessary for stable Foxp3 expression. However, Ifnγ^-/-Socs1^-/- Treg cells had hyperactivated STAT3 and higher IL-17A (IL-17) production compared with Ifnγ^-/-Socs1^+/+ Treg cells and could not suppress colitis induced by naive T cells in Rag2^-/- mice. In vitro experiments suggested that cytokines produced by Socs1^-/- T_reg cells and Ifnγ^-/-Socs1^-/- T_reg cells modulated antigen-presenting cells for preferential Th1 and Th17 induction, respectively. We propose that SOCS1 plays important roles in T_reg cell integrity and function by maintaining Foxp3 expression and by suppressing IFN-γ and IL-17 production driven by STAT1 and STAT3, respectively. © 2011 Takahashi et al.</p>

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SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-γ and IL-17A production

Takahashi Reiko, Nishimoto Shuhei, Muto Go, Sekiya Takashi, Tamiya Taiga, Kimura Akihiro, Morita Rimpei, Asakawa Mayako, Chinen Takatoshi, Yoshimura Akihiko

Journal of Experimental Medicine 208 （ 10 ） 2055 - 2067 2011年09月

ISSN  0022-1007

　概要を見る

<p>Regulatory T cells (T_reg cells) maintain immune homeostasis by limiting inflammatory responses. SOCS1 (suppressor of cytokine signaling 1), a negative regulator of cytokine signaling, is necessary for the suppressor functions of T_reg cells in vivo, yet detailed mechanisms remain to be clarified. We found that Socs1^-/- Treg cells produced high levels of IFN-γ and rapidly lost Foxp3 when transferred into Rag2^-/- mice or cultured in vitro, even though the CNS2 (conserved noncoding DNA sequence 2) in the Foxp3 enhancer region was fully demethylated. Socs1^-/- T_reg cells showed hyperactivation of STAT1 and STAT3. Because Foxp3 expression was stable and STAT1 activation was at normal levels in Ifnγ^-/-Socs1^-/- T_reg cells, the restriction of IFN-γ-STAT1 signaling by SOCS1 is suggested to be necessary for stable Foxp3 expression. However, Ifnγ^-/-Socs1^-/- Treg cells had hyperactivated STAT3 and higher IL-17A (IL-17) production compared with Ifnγ^-/-Socs1^+/+ Treg cells and could not suppress colitis induced by naive T cells in Rag2^-/- mice. In vitro experiments suggested that cytokines produced by Socs1^-/- T_reg cells and Ifnγ^-/-Socs1^-/- T_reg cells modulated antigen-presenting cells for preferential Th1 and Th17 induction, respectively. We propose that SOCS1 plays important roles in T_reg cell integrity and function by maintaining Foxp3 expression and by suppressing IFN-γ and IL-17 production driven by STAT1 and STAT3, respectively. © 2011 Takahashi et al.</p>

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Desmoglein 3-specific CD4⁺ T cells induce pemphigus vulgaris and interface dermatitis in mice

Takahashi Hayato, Kouno Michiyoshi, Nagao Keisuke, Wada Naoko, Hata Tsuyoshi, Nishimoto Shuhei, Iwakura Yoichiro, Yoshimura Akihiko, Yamada Taketo, Kuwana Masataka, Fujii Hideki, Koyasu Shigeo, Amagai Masayuki

Journal of Clinical Investigation 121 （ 9 ） 3677 - 3688 2011年09月

ISSN  0021-9738

　概要を見る

<p>Pemphigus vulgaris (PV) is a severe autoimmune disease involving blistering of the skin and mucous membranes. It is caused by autoantibodies against desmoglein 3 (Dsg3), an adhesion molecule critical for maintaining epithelial integrity in the skin, oral mucosa, and esophagus. Knowing the antigen targeted by the autoantibodies renders PV a valuable model of autoimmunity. Recently, a role for Dsg3-specific CD4⁺ T helper cells in autoantibody production was demonstrated in a mouse model of PV, but whether these cells exert cytotoxicity in the tissues is unclear. Here, we analyzed 3 Dsg3-specific TCRs using transgenic mice and retrovirus induction. Dsg3-specific transgenic (Dsg3H1) T cells underwent deletion in the presence of Dsg3 in vivo. Dsg3H1 T cells that developed in the absence of Dsg3 elicited a severe pemphigus-like phenotype when cotransferred into immunodeficient mice with B cells from Dsg3^-/- mice. Strikingly, in addition to humoral responses, T cell infiltration of Dsg3-expressing tissues led to interface dermatitis, a distinct form of T cell-mediated autoimmunity that causes keratinocyte apoptosis and is seen in various inflammatory/autoimmune skin diseases, including paraneoplastic pemphigus. The use of retrovirally generated Dsg3-specific T cells revealed that interface dermatitis occurred in an IFN-γ- and TCR avidity-dependent manner. This model of autoimmunity demonstrates that T cells specific for a physiological skin-associated autoantigen are capable of inducing interface dermatitis and should provide a valuable tool for further exploring the immunopathophysiology of T cell-mediated skin diseases.</p>

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Desmoglein 3-specific CD4⁺ T cells induce pemphigus vulgaris and interface dermatitis in mice

Takahashi Hayato, Kouno Michiyoshi, Nagao Keisuke, Wada Naoko, Hata Tsuyoshi, Nishimoto Shuhei, Iwakura Yoichiro, Yoshimura Akihiko, Yamada Taketo, Kuwana Masataka, Fujii Hideki, Koyasu Shigeo, Amagai Masayuki

Journal of Clinical Investigation 121 （ 9 ） 3677 - 3688 2011年09月

ISSN  0021-9738

　概要を見る

<p>Pemphigus vulgaris (PV) is a severe autoimmune disease involving blistering of the skin and mucous membranes. It is caused by autoantibodies against desmoglein 3 (Dsg3), an adhesion molecule critical for maintaining epithelial integrity in the skin, oral mucosa, and esophagus. Knowing the antigen targeted by the autoantibodies renders PV a valuable model of autoimmunity. Recently, a role for Dsg3-specific CD4⁺ T helper cells in autoantibody production was demonstrated in a mouse model of PV, but whether these cells exert cytotoxicity in the tissues is unclear. Here, we analyzed 3 Dsg3-specific TCRs using transgenic mice and retrovirus induction. Dsg3-specific transgenic (Dsg3H1) T cells underwent deletion in the presence of Dsg3 in vivo. Dsg3H1 T cells that developed in the absence of Dsg3 elicited a severe pemphigus-like phenotype when cotransferred into immunodeficient mice with B cells from Dsg3^-/- mice. Strikingly, in addition to humoral responses, T cell infiltration of Dsg3-expressing tissues led to interface dermatitis, a distinct form of T cell-mediated autoimmunity that causes keratinocyte apoptosis and is seen in various inflammatory/autoimmune skin diseases, including paraneoplastic pemphigus. The use of retrovirally generated Dsg3-specific T cells revealed that interface dermatitis occurred in an IFN-γ- and TCR avidity-dependent manner. This model of autoimmunity demonstrates that T cells specific for a physiological skin-associated autoantigen are capable of inducing interface dermatitis and should provide a valuable tool for further exploring the immunopathophysiology of T cell-mediated skin diseases.</p>

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Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells

Sujino Tomohisa, Kanai Takanori, Ono Yuichi, Mikami Yohei, Hayashi Atsushi, Doi Tomomitsu, Matsuoka Katsuyoshi, Hisamatsu Tadakazu, Takaishi Hiromasa, Ogata Haruhiko, Yoshimura Akihiko, Littman Dan R., Hibi Toshifumi

Gastroenterology 141 （ 3 ） 1014 - 1023 2011年09月

ISSN  0016-5085

　概要を見る

<p>Background &amp; Aims: Although T-helper (Th) 17 and Th1 cells are involved in pathogenesis of intestinal inflammation, their developmental pathways and sufficiency to promote disease are not known; nor are the roles of CD4 ⁺CD25 ⁺ regulatory T (T _R) cells in their development. Methods: We performed adoptive transfer experiments to investigate the induction and suppression of colitis using nave CD4 ⁺CD45RB ^high T cells and/or CD4 ⁺CD25 ⁺ T _R cells that were obtained from retinoid-related orphan receptor gamma t (RORγt) gfp/ ⁺ or Ly5.1/Ly5.2 congenic mice. Results: We observed 3 types of colitogenic CD4 ⁺ Th1 cells (interleukin [IL]-17A ^-interferon [IFN]-γ ⁺): RORγt classical Th1 cells that differentiated directly from nave T cells; RORγt ⁺ Th1-like cells; and RORγt alternative Th1 cells that were terminally differentiated from RORγt ⁺ cells via Th17 (IL-17A ⁺IFN-γ), Th17/Th1 (IL-17A ⁺IFN- γ ⁺), or Th1-like (IL-17AIFN-γ ⁺) cells. In this pathway, CD4 ⁺CD25 ⁺ T _R cells suppress the development of not only classical Th1 cells, but also alternative Th1 cells at the transition of Th17/Th1 into alternative Th1 cells, resulting in accumulation of Th17 and Th17/Th1 cells in mice in which the development of colitis was suppressed. Furthermore, T _R cells regulated the established balance of Th17 and Th1 cells under colitic conditions to yield a high ratio of Th17 and Th17/Th1 cells to Th1 cells in noncolitic conditions. Conclusions: Th17 and Th17/Th1 cells become colitogenic alternative Th1 cells via Th17, Th17/Th1, and Th1-like cells, independently of classical Th1 cells. T _R cells suppress this pathway, resulting in accumulation of Th17 and Th17/Th1 cells. © 2011 AGA Institute.</p>

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1,25-Dihydroxyvitamin D ₃ ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A

Joshi Sneha, Pantalena Luiz Carlos, Liu Xikui K., Gaffen Sarah L., Liu Hong, Rohowsky-Kochan Christine, Ichiyama Kenji, Yoshimura Akihiko, Steinman Lawrence, Christakos Sylvia, Youssef Sawsan

Molecular and Cellular Biology 31 （ 17 ） 3653 - 3669 2011年09月

ISSN  0270-7306

　概要を見る

<p>A new class of inflammatory CD4 ⁺ T cells that produce interleukin-17 (IL-17) (termed Th17) has been identified, which plays a critical role in numerous inflammatory conditions and autoimmune diseases. The active form of vitamin D, 1,25-dihydroxyvitamin D ₃ [1,25(OH) ₂D ₃], has a direct repressive effect on the expression of IL-17A in both human and mouse T cells. In vivo treatment of mice with ongoing experimental autoimmune encephalomyelitis (EAE; a mouse model of multiple sclerosis) diminishes paralysis and progression of the disease and reduces IL-17A-secreting CD4 ⁺ T cells in the periphery and central nervous system (CNS). The mechanism of 1,25(OH) ₂D ₃ repression of IL-17A expression was found to be transcriptional repression, mediated by the vitamin D receptor (VDR). Transcription assays, gel shifting, and chromatin immunoprecipitation (ChIP) assays indicate that the negative effect of 1,25(OH) ₂D ₃ on IL-17A involves blocking of nuclear factor for activated T cells (NFAT), recruitment of histone deacetylase (HDAC), sequestration of Runt-related transcription factor 1 (Runx1) by 1,25(OH) ₂D ₃/VDR, and a direct effect of 1,25(OH) ₂D ₃ on induction of Foxp3. Our results describe novel mechanisms and new concepts with regard to vitamin D and the immune system and suggest therapeutic targets for the control of autoimmune diseases. © 2011, American Society for Microbiology.</p>

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Regulatory T cells suppress development of colitis, blocking differentiation of T-helper 17 into alternative T-helper 1 cells

Sujino Tomohisa, Kanai Takanori, Ono Yuichi, Mikami Yohei, Hayashi Atsushi, Doi Tomomitsu, Matsuoka Katsuyoshi, Hisamatsu Tadakazu, Takaishi Hiromasa, Ogata Haruhiko, Yoshimura Akihiko, Littman Dan R., Hibi Toshifumi

Gastroenterology 141 （ 3 ） 1014 - 1023 2011年09月

ISSN  0016-5085

　概要を見る

<p>Background &amp; Aims: Although T-helper (Th) 17 and Th1 cells are involved in pathogenesis of intestinal inflammation, their developmental pathways and sufficiency to promote disease are not known; nor are the roles of CD4 ⁺CD25 ⁺ regulatory T (T _R) cells in their development. Methods: We performed adoptive transfer experiments to investigate the induction and suppression of colitis using nave CD4 ⁺CD45RB ^high T cells and/or CD4 ⁺CD25 ⁺ T _R cells that were obtained from retinoid-related orphan receptor gamma t (RORγt) gfp/ ⁺ or Ly5.1/Ly5.2 congenic mice. Results: We observed 3 types of colitogenic CD4 ⁺ Th1 cells (interleukin [IL]-17A ^-interferon [IFN]-γ ⁺): RORγt classical Th1 cells that differentiated directly from nave T cells; RORγt ⁺ Th1-like cells; and RORγt alternative Th1 cells that were terminally differentiated from RORγt ⁺ cells via Th17 (IL-17A ⁺IFN-γ), Th17/Th1 (IL-17A ⁺IFN- γ ⁺), or Th1-like (IL-17AIFN-γ ⁺) cells. In this pathway, CD4 ⁺CD25 ⁺ T _R cells suppress the development of not only classical Th1 cells, but also alternative Th1 cells at the transition of Th17/Th1 into alternative Th1 cells, resulting in accumulation of Th17 and Th17/Th1 cells in mice in which the development of colitis was suppressed. Furthermore, T _R cells regulated the established balance of Th17 and Th1 cells under colitic conditions to yield a high ratio of Th17 and Th17/Th1 cells to Th1 cells in noncolitic conditions. Conclusions: Th17 and Th17/Th1 cells become colitogenic alternative Th1 cells via Th17, Th17/Th1, and Th1-like cells, independently of classical Th1 cells. T _R cells suppress this pathway, resulting in accumulation of Th17 and Th17/Th1 cells. © 2011 AGA Institute.</p>

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1,25-Dihydroxyvitamin D ₃ ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A

Joshi Sneha, Pantalena Luiz Carlos, Liu Xikui K., Gaffen Sarah L., Liu Hong, Rohowsky-Kochan Christine, Ichiyama Kenji, Yoshimura Akihiko, Steinman Lawrence, Christakos Sylvia, Youssef Sawsan

Molecular and Cellular Biology 31 （ 17 ） 3653 - 3669 2011年09月

ISSN  0270-7306

　概要を見る

<p>A new class of inflammatory CD4 ⁺ T cells that produce interleukin-17 (IL-17) (termed Th17) has been identified, which plays a critical role in numerous inflammatory conditions and autoimmune diseases. The active form of vitamin D, 1,25-dihydroxyvitamin D ₃ [1,25(OH) ₂D ₃], has a direct repressive effect on the expression of IL-17A in both human and mouse T cells. In vivo treatment of mice with ongoing experimental autoimmune encephalomyelitis (EAE; a mouse model of multiple sclerosis) diminishes paralysis and progression of the disease and reduces IL-17A-secreting CD4 ⁺ T cells in the periphery and central nervous system (CNS). The mechanism of 1,25(OH) ₂D ₃ repression of IL-17A expression was found to be transcriptional repression, mediated by the vitamin D receptor (VDR). Transcription assays, gel shifting, and chromatin immunoprecipitation (ChIP) assays indicate that the negative effect of 1,25(OH) ₂D ₃ on IL-17A involves blocking of nuclear factor for activated T cells (NFAT), recruitment of histone deacetylase (HDAC), sequestration of Runt-related transcription factor 1 (Runx1) by 1,25(OH) ₂D ₃/VDR, and a direct effect of 1,25(OH) ₂D ₃ on induction of Foxp3. Our results describe novel mechanisms and new concepts with regard to vitamin D and the immune system and suggest therapeutic targets for the control of autoimmune diseases. © 2011, American Society for Microbiology.</p>

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Silencing suppressor of cytokine signaling-1 (SOCS1) in macrophages improves Mycobacterium tuberculosis control in an interferon-γ (IFN-γ)-dependent manner

Carow Berit, Ye Xiang Qun, Gavier-Wide Dolores, Bhuju Sabin, Oehlmann Wulf, Singh Mahavir, Sköld Markus, Ignatowicz Lech, Yoshimura Akihiko, Wigzell Hans, Rottenberg Martin E.

Journal of Biological Chemistry 286 （ 30 ） 26873 - 26887 2011年07月

ISSN  0021-9258

　概要を見る

<p>Protection against infection with Mycobacterium tuberculosis demands IFN-γ. SOCS1 has been shown to inhibit responses to IFN-γ and might thereby play a central role in the outcome of infection. We found that M. tuberculosis is a highly efficient stimulator of SOCS1 expression in murine and human macrophages and in tissues from infected mice. Surprisingly, SOCS1 reduced responses to IL-12, resulting in an impaired IFN-γ secretion by macrophages that in turn accounted for a deteriorated intracellular mycobacterial control. Despite SOCS1 expression, mycobacteria-infected macrophages responded to exogenously added IFN-γ. SOCS1 attenuated the expression of the majority of genes modulated by M. tuberculosis infection of macrophages. Using a conditional knockdown strategy in mice, we found that SOCS1 expression by macrophages hampered M. tuberculosis clearance early after infection in vivo in an IFN-γ-dependent manner. On the other hand, at later time points, SOCS1 expression by non-macrophage cells protected the host from infection-induced detrimental inflammation. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.</p>

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Silencing suppressor of cytokine signaling-1 (SOCS1) in macrophages improves Mycobacterium tuberculosis control in an interferon-γ (IFN-γ)-dependent manner

Carow Berit, Ye Xiang Qun, Gavier-Wide Dolores, Bhuju Sabin, Oehlmann Wulf, Singh Mahavir, Sköld Markus, Ignatowicz Lech, Yoshimura Akihiko, Wigzell Hans, Rottenberg Martin E.

Journal of Biological Chemistry 286 （ 30 ） 26873 - 26887 2011年07月

ISSN  0021-9258

　概要を見る

<p>Protection against infection with Mycobacterium tuberculosis demands IFN-γ. SOCS1 has been shown to inhibit responses to IFN-γ and might thereby play a central role in the outcome of infection. We found that M. tuberculosis is a highly efficient stimulator of SOCS1 expression in murine and human macrophages and in tissues from infected mice. Surprisingly, SOCS1 reduced responses to IL-12, resulting in an impaired IFN-γ secretion by macrophages that in turn accounted for a deteriorated intracellular mycobacterial control. Despite SOCS1 expression, mycobacteria-infected macrophages responded to exogenously added IFN-γ. SOCS1 attenuated the expression of the majority of genes modulated by M. tuberculosis infection of macrophages. Using a conditional knockdown strategy in mice, we found that SOCS1 expression by macrophages hampered M. tuberculosis clearance early after infection in vivo in an IFN-γ-dependent manner. On the other hand, at later time points, SOCS1 expression by non-macrophage cells protected the host from infection-induced detrimental inflammation. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.</p>

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miR126 positively regulates mast cell proliferation and cytokine production through suppressing Spred1

Ishizaki Takuma, Tamiya Taiga, Taniguchi Koji, Morita Rimpei, Kato Reiko, Okamoto Fuyuki, Saeki Kazuko, Nomura Masatoshi, Nojima Yoshihisa, Yoshimura Akihiko

Genes to Cells 16 （ 7 ） 803 - 814 2011年07月

ISSN  1356-9597

　概要を見る

<p>The protein known as Spred1 (Sprouty-related Ena/VASP homology-1 domain-containing protein) has been identified as a negative regulator of growth factor-induced ERK/mitogen-activated protein kinase activation. Spred1 has also been implicated as the target of microRNA-126 (miR126), a miRNA located within the Egfl7 gene, and is involved in the regulation of vessel development through its role in regulating VEGF signaling. In this study, we examined the role of miR126 and Spred1 in the hematopoietic system, as miR126 has been shown to be overexpressed in leukemic cells. miR126 levels were down-regulated during mast cell differentiation from bone marrow cells, whereas Spred1 expression was inversely up-regulated. Overexpression of miR126 suppressed Spred1 expression and enhanced ERK activity in primary bone marrow cells and MC9 mast cells, which were associated with elevated FcεRI-mediated cytokine production. To confirm the effect of Spred1 reduction in vivo, we generated hematopoietic cell-specific Spred1-conditional knockout mice. These mice showed increased numbers of mast cells, and Spred1-deficient bone marrow-derived mast cells were highly activated by cross-linking of Fcε-R stimulation as well as by IL-3 and SCF stimulation. These results suggest that Spred1 negatively regulates mast cell activation, which is modulated by miR126. © 2011 The Authors. Journal compilation © 2011 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.</p>

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miR126 positively regulates mast cell proliferation and cytokine production through suppressing Spred1

Ishizaki Takuma, Tamiya Taiga, Taniguchi Koji, Morita Rimpei, Kato Reiko, Okamoto Fuyuki, Saeki Kazuko, Nomura Masatoshi, Nojima Yoshihisa, Yoshimura Akihiko

Genes to Cells 16 （ 7 ） 803 - 814 2011年07月

ISSN  1356-9597

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<p>The protein known as Spred1 (Sprouty-related Ena/VASP homology-1 domain-containing protein) has been identified as a negative regulator of growth factor-induced ERK/mitogen-activated protein kinase activation. Spred1 has also been implicated as the target of microRNA-126 (miR126), a miRNA located within the Egfl7 gene, and is involved in the regulation of vessel development through its role in regulating VEGF signaling. In this study, we examined the role of miR126 and Spred1 in the hematopoietic system, as miR126 has been shown to be overexpressed in leukemic cells. miR126 levels were down-regulated during mast cell differentiation from bone marrow cells, whereas Spred1 expression was inversely up-regulated. Overexpression of miR126 suppressed Spred1 expression and enhanced ERK activity in primary bone marrow cells and MC9 mast cells, which were associated with elevated FcεRI-mediated cytokine production. To confirm the effect of Spred1 reduction in vivo, we generated hematopoietic cell-specific Spred1-conditional knockout mice. These mice showed increased numbers of mast cells, and Spred1-deficient bone marrow-derived mast cells were highly activated by cross-linking of Fcε-R stimulation as well as by IL-3 and SCF stimulation. These results suggest that Spred1 negatively regulates mast cell activation, which is modulated by miR126. © 2011 The Authors. Journal compilation © 2011 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.</p>

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Transcription Factor Smad-Independent T Helper 17 Cell Induction by Transforming-Growth Factor-β Is Mediated by Suppression of Eomesodermin

Ichiyama Kenji, Sekiya Takashi, Inoue Naoko, Tamiya Taiga, Kashiwagi Ikko, Kimura Akihiro, Morita Rimpei, Muto Go, Shichita Takashi, Takahashi Reiko, Yoshimura Akihiko

Immunity 34 （ 5 ） 741 - 754 2011年05月

ISSN  1074-7613

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<p>Transforming growth factor-β (TGF-β) has been shown to be required for Th17 cell differentiation via Smad-independent mechanisms. The molecular mechanism underlying this pathway remains to be clarified, however. We searched for genes regulated by TGF-β through the Smad-independent pathway by using Smad2 and Smad3 double-deficient T cells and identified the transcription factor Eomesodermin (Eomes), whose expression was suppressed by TGF-β via the c-Jun N-terminal kinase (JNK)-c-Jun signaling pathway. Inhibition of JNK strongly suppressed disease in an in vivo EAE model as well as in vitro Th17 cell induction. Overexpression of Eomes substantially suppressed Th17 cell differentiation, whereas ablation of Eomes expression could substitute for TGF-β in Th17 cell induction in primary T cells. Eomes suppressed Rorc and Il17a promoters by directly binding to the proximal region of these promoters. In conclusion, the suppression of Eomes by TGF-β via the JNK pathway is an important mechanism for Smad-independent Th17 cell differentiation. © 2011 Elsevier Inc.</p>

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Transcription Factor Smad-Independent T Helper 17 Cell Induction by Transforming-Growth Factor-β Is Mediated by Suppression of Eomesodermin

Ichiyama Kenji, Sekiya Takashi, Inoue Naoko, Tamiya Taiga, Kashiwagi Ikko, Kimura Akihiro, Morita Rimpei, Muto Go, Shichita Takashi, Takahashi Reiko, Yoshimura Akihiko

Immunity 34 （ 5 ） 741 - 754 2011年05月

ISSN  1074-7613

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<p>Transforming growth factor-β (TGF-β) has been shown to be required for Th17 cell differentiation via Smad-independent mechanisms. The molecular mechanism underlying this pathway remains to be clarified, however. We searched for genes regulated by TGF-β through the Smad-independent pathway by using Smad2 and Smad3 double-deficient T cells and identified the transcription factor Eomesodermin (Eomes), whose expression was suppressed by TGF-β via the c-Jun N-terminal kinase (JNK)-c-Jun signaling pathway. Inhibition of JNK strongly suppressed disease in an in vivo EAE model as well as in vitro Th17 cell induction. Overexpression of Eomes substantially suppressed Th17 cell differentiation, whereas ablation of Eomes expression could substitute for TGF-β in Th17 cell induction in primary T cells. Eomes suppressed Rorc and Il17a promoters by directly binding to the proximal region of these promoters. In conclusion, the suppression of Eomes by TGF-β via the JNK pathway is an important mechanism for Smad-independent Th17 cell differentiation. © 2011 Elsevier Inc.</p>

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

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

American Journal of Physiology - Regulatory Integrative and Comparative Physiology 300 （ 5 ）  2011年05月

ISSN  0363-6119

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

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

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

Arteriosclerosis, Thrombosis, and Vascular Biology 31 （ 5 ） 980 - 985 2011年05月

ISSN  1079-5642

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

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