Papers - Yoshimura, Akihiko

Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke

Shichita Takashi, Ago Tetsuro, Kamouchi Masahiro, Kitazono Takanari, Yoshimura Akihiko, Ooboshi Hiroaki

Journal of Neurochemistry 123 ( SUPPL. 2 ) 29 - 38 2012.11

ISSN  0022-3042

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<p>Post-ischemic inflammation is an essential step in the progression of ischemic stroke. This review focuses on the function of infiltrating immune cells, macrophages, and T cells, in ischemic brain injury. The brain is a sterile organ; however, the activation of Toll-like receptor (TLR) 2 and TLR4 is pivotal in the beginning of post-ischemic inflammation. Some endogenous TLR ligands are released from injured brain cells, including high mobility group box 1 and peroxiredoxin family proteins, and activate the infiltrating macrophages and induce the expression of inflammatory cytokines. Following this step, T cells also infiltrate into the ischemic brain and mediate post-ischemic inflammation in the delayed phase. Various cytokines from helper T cells and _γδT cells function as neurotoxic (IL-23/IL-17, IFN- _γ) or neuroprotective (IL-10, IL-4) mediators. Novel neuroprotective strategies should therefore be developed through more detailed understanding of this process and the regulation of post-ischemic inflammation. © 2012 International Society for Neurochemistry.</p>

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Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke

Shichita Takashi, Ago Tetsuro, Kamouchi Masahiro, Kitazono Takanari, Yoshimura Akihiko, Ooboshi Hiroaki

Journal of Neurochemistry 123 ( SUPPL. 2 ) 29 - 38 2012.11

ISSN  0022-3042

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<p>Post-ischemic inflammation is an essential step in the progression of ischemic stroke. This review focuses on the function of infiltrating immune cells, macrophages, and T cells, in ischemic brain injury. The brain is a sterile organ; however, the activation of Toll-like receptor (TLR) 2 and TLR4 is pivotal in the beginning of post-ischemic inflammation. Some endogenous TLR ligands are released from injured brain cells, including high mobility group box 1 and peroxiredoxin family proteins, and activate the infiltrating macrophages and induce the expression of inflammatory cytokines. Following this step, T cells also infiltrate into the ischemic brain and mediate post-ischemic inflammation in the delayed phase. Various cytokines from helper T cells and _γδT cells function as neurotoxic (IL-23/IL-17, IFN- _γ) or neuroprotective (IL-10, IL-4) mediators. Novel neuroprotective strategies should therefore be developed through more detailed understanding of this process and the regulation of post-ischemic inflammation. © 2012 International Society for Neurochemistry.</p>

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STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

Sekine Y., Ikeda O., Mizushima A., Ueno Y., Muromoto R., Yoshimura A., Kanakura Y., Oritani K., Matsuda T.

Oncogene 31 ( 40 ) 4384 - 4396 2012.10

ISSN  0950-9232

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<p>In chronic myeloid leukemia (CML), the BCR-ABL fusion oncoprotein activates multiple pathways involved in cell survival, growth promotion and disease progression. In this report, we show that the signal-transducing adaptor protein-2 (STAP-2) is involved in BCR-ABL activity. We demonstrate that STAP-2 bound to BCR-ABL, and BCR and ABL proteins, depending on the STAP-2 Src homology 2-like domain. BCR-ABL phosphorylates STAP-2 Tyr250 and the phosphorylated STAP-2 in turn upregulated BCR-ABL phosphorylation, leading to enhanced activation of downstream signaling molecules including ERK (extracellular- signal-regulated kinase), STAT5 (signal transducer and activator of transcription 5), BCL-xL (B-cell lymphoma-extra large) and BCL-2(B-cell lymphoma 2). In addition, STAP-2 interacts with BCR-ABL to alter chemokine receptor expression leading to downregulation of CXCR4 and upregulation of CCR7. The interaction between STAP-2 and BCR-ABL plays a crucial role in conferring a growth advantage and resistance to imatinib, a BCR-ABL inhibitor, as well as tumor progression. Notably, mice injected with BCR-ABL/STAP-2-expressing Ba/F3 cells developed lymph node enlargement and hepatosplenomegaly. Moreover, suppression of STAP-2 in K562 CML cells resulted in no tumor formation in mice. Our results demonstrate a critical contribution of STAP-2 in BCR-ABL activity, and suggest that STAP-2 might be an important candidate for drug development for patients with CML. Furthermore, the expression of STAP-2 provides useful information for estimating the characteristics of individual CML clones. © 2012 Macmillan Publishers Limited.</p>

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STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

Sekine Y., Ikeda O., Mizushima A., Ueno Y., Muromoto R., Yoshimura A., Kanakura Y., Oritani K., Matsuda T.

Oncogene 31 ( 40 ) 4384 - 4396 2012.10

ISSN  0950-9232

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<p>In chronic myeloid leukemia (CML), the BCR-ABL fusion oncoprotein activates multiple pathways involved in cell survival, growth promotion and disease progression. In this report, we show that the signal-transducing adaptor protein-2 (STAP-2) is involved in BCR-ABL activity. We demonstrate that STAP-2 bound to BCR-ABL, and BCR and ABL proteins, depending on the STAP-2 Src homology 2-like domain. BCR-ABL phosphorylates STAP-2 Tyr250 and the phosphorylated STAP-2 in turn upregulated BCR-ABL phosphorylation, leading to enhanced activation of downstream signaling molecules including ERK (extracellular- signal-regulated kinase), STAT5 (signal transducer and activator of transcription 5), BCL-xL (B-cell lymphoma-extra large) and BCL-2(B-cell lymphoma 2). In addition, STAP-2 interacts with BCR-ABL to alter chemokine receptor expression leading to downregulation of CXCR4 and upregulation of CCR7. The interaction between STAP-2 and BCR-ABL plays a crucial role in conferring a growth advantage and resistance to imatinib, a BCR-ABL inhibitor, as well as tumor progression. Notably, mice injected with BCR-ABL/STAP-2-expressing Ba/F3 cells developed lymph node enlargement and hepatosplenomegaly. Moreover, suppression of STAP-2 in K562 CML cells resulted in no tumor formation in mice. Our results demonstrate a critical contribution of STAP-2 in BCR-ABL activity, and suggest that STAP-2 might be an important candidate for drug development for patients with CML. Furthermore, the expression of STAP-2 provides useful information for estimating the characteristics of individual CML clones. © 2012 Macmillan Publishers Limited.</p>

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Deleterious effect of the IL-23/IL-17A axis and γδT cells on left ventricular remodeling after myocardial infarction.

Yan Xiaoxiang, Shichita Takashi, Katsumata Yoshinori, Matsuhashi Tomohiro, Ito Hideyuki, Ito Kentaro, Anzai Atsushi, Endo Jin, Tamura Yuichi, Kimura Kensuke, Fujita Jun, Shinmura Ken, Shen Weifeng, Yoshimura Akihiko, Fukuda Keiichi, Sano Motoaki

Journal of the American Heart Association 1 ( 5 )  2012.10

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<p>Left ventricular (LV) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction (MI). At the present time, therapeutic options to prevent LV remodeling are limited. We created a large MI by permanent ligation of the coronary artery and identified a potential link between the interleukin (IL)-23/IL-17A axis and γδT cells that affects late-stage LV remodeling after MI. Despite the finsinf that infarct size 24 hours after surgery was similar to that in wild-type mice, a deficiency in IL-23, IL-17A, or γδT cells improved survival after 7 days, limiting infarct expansion and fibrosis in noninfarcted myocardium and alleviating LV dilatation and systolic dysfunction on day 28 post-MI. M(1) macrophages and neutrophils were the major cellular source of IL-23, whereas &gt;90% of IL-17A-producing T cells in infarcted heart were CD4(-) TCRγδ(+) (γδT) cells. Toll-like receptor signaling and IL-1β worked in concert with IL-23 to drive expansion and IL-17A production in cardiac γδT cells, whereas the sphingosine-1-phosphate receptor and CCL20/CCR6 signaling pathways mediated γδT cell recruitment into infarcted heart. IL-17A was not involved in the acute inflammatory response, but it functioned specifically in the late remodeling stages by promoting sustained infiltration of neutrophils and macrophages, stimulating macrophages to produce proinflammatory cytokines, aggravating cardiomyocyte death, and enhancing fibroblast proliferation and profibrotic gene expression. The IL-23/IL-17A immune axis and γδT cells are potentially promising therapeutic targets after MI to prevent progression to end-stage dilated cardiomyopathy.</p>

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Deleterious effect of the IL-23/IL-17A axis and γδT cells on left ventricular remodeling after myocardial infarction.

Yan Xiaoxiang, Shichita Takashi, Katsumata Yoshinori, Matsuhashi Tomohiro, Ito Hideyuki, Ito Kentaro, Anzai Atsushi, Endo Jin, Tamura Yuichi, Kimura Kensuke, Fujita Jun, Shinmura Ken, Shen Weifeng, Yoshimura Akihiko, Fukuda Keiichi, Sano Motoaki

Journal of the American Heart Association 1 ( 5 )  2012.10

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<p>Left ventricular (LV) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction (MI). At the present time, therapeutic options to prevent LV remodeling are limited. We created a large MI by permanent ligation of the coronary artery and identified a potential link between the interleukin (IL)-23/IL-17A axis and γδT cells that affects late-stage LV remodeling after MI. Despite the finsinf that infarct size 24 hours after surgery was similar to that in wild-type mice, a deficiency in IL-23, IL-17A, or γδT cells improved survival after 7 days, limiting infarct expansion and fibrosis in noninfarcted myocardium and alleviating LV dilatation and systolic dysfunction on day 28 post-MI. M(1) macrophages and neutrophils were the major cellular source of IL-23, whereas &gt;90% of IL-17A-producing T cells in infarcted heart were CD4(-) TCRγδ(+) (γδT) cells. Toll-like receptor signaling and IL-1β worked in concert with IL-23 to drive expansion and IL-17A production in cardiac γδT cells, whereas the sphingosine-1-phosphate receptor and CCL20/CCR6 signaling pathways mediated γδT cell recruitment into infarcted heart. IL-17A was not involved in the acute inflammatory response, but it functioned specifically in the late remodeling stages by promoting sustained infiltration of neutrophils and macrophages, stimulating macrophages to produce proinflammatory cytokines, aggravating cardiomyocyte death, and enhancing fibroblast proliferation and profibrotic gene expression. The IL-23/IL-17A immune axis and γδT cells are potentially promising therapeutic targets after MI to prevent progression to end-stage dilated cardiomyopathy.</p>

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Spred-2 deficiency exacerbates acetaminophen-induced hepatotoxicity in mice

Wakabayashi Hiroshi, Ito Toshihiro, Fushimi Soichiro, Nakashima Yuki, Itakura Jyunya, Qiuying Liu, Win Min Min, Cuiming Sun, Chen Cao, Sato Miwa, Mino Megumi, Ogino Tetsuya, Makino Hirofumi, Yoshimura Akihiko, Matsukawa Akihiro

Clinical Immunology 144 ( 3 ) 272 - 282 2012.09

ISSN  1521-6616

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<p>MAPKs are involved in acetaminophen (APAP)-hepatotoxicity, but the regulatory mechanism remains unknown. Here, we explored the role of Spred-2 that negatively regulates Ras/ERK pathway in APAP-hepatotoxicity. Spred-2 knockout (KO) mice demonstrated exacerbated liver injury, an event that was associated with increased numbers of CD4 ⁺ T, CD8 ⁺ T and NK cells in the liver compared to the control. Levels of CXCL9/CXCL10 that attract and activate these cells were increased in Spred-2 KO-liver. Kupffer cells isolated from Spred-2 KO mice after APAP challenge expressed higher levels of CXCL9/CXCL10 than those from the control. Upon stimulation with APAP or IFNγ, naïve Kupffer cells from Spred-2 KO mice expressed higher levels of CXCL9/CXCL10. NK cell-depletion attenuated APAP-hepatotoxicity with lowered hepatic IFNγ and decreased numbers of not only NK cells but also CD4 ⁺ T and CD8 ⁺ T cells in the liver. These results suggest that Spred-2 negatively regulates APAP-hepatotoxicity under the control of Kupffer cells and NK cells. © 2012 Elsevier Inc.</p>

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Spred-2 deficiency exacerbates acetaminophen-induced hepatotoxicity in mice

Wakabayashi Hiroshi, Ito Toshihiro, Fushimi Soichiro, Nakashima Yuki, Itakura Jyunya, Qiuying Liu, Win Min Min, Cuiming Sun, Chen Cao, Sato Miwa, Mino Megumi, Ogino Tetsuya, Makino Hirofumi, Yoshimura Akihiko, Matsukawa Akihiro

Clinical Immunology 144 ( 3 ) 272 - 282 2012.09

ISSN  1521-6616

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<p>MAPKs are involved in acetaminophen (APAP)-hepatotoxicity, but the regulatory mechanism remains unknown. Here, we explored the role of Spred-2 that negatively regulates Ras/ERK pathway in APAP-hepatotoxicity. Spred-2 knockout (KO) mice demonstrated exacerbated liver injury, an event that was associated with increased numbers of CD4 ⁺ T, CD8 ⁺ T and NK cells in the liver compared to the control. Levels of CXCL9/CXCL10 that attract and activate these cells were increased in Spred-2 KO-liver. Kupffer cells isolated from Spred-2 KO mice after APAP challenge expressed higher levels of CXCL9/CXCL10 than those from the control. Upon stimulation with APAP or IFNγ, naïve Kupffer cells from Spred-2 KO mice expressed higher levels of CXCL9/CXCL10. NK cell-depletion attenuated APAP-hepatotoxicity with lowered hepatic IFNγ and decreased numbers of not only NK cells but also CD4 ⁺ T and CD8 ⁺ T cells in the liver. These results suggest that Spred-2 negatively regulates APAP-hepatotoxicity under the control of Kupffer cells and NK cells. © 2012 Elsevier Inc.</p>

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Loss of Pdk1-Foxo1 signaling in myeloid cells predisposes to adipose tissue inflammation and insulin resistance

Kawano Yoshinaga, Nakae Jun, Watanabe Nobuyuki, Fujisaka Shiho, Iskandar Kristy, Sekioka Risa, Hayashi Yoshitake, Tobe Kazuyuki, Kasuga Masato, Noda Tetsuo, Yoshimura Akihiko, Onodera Masafumi, Itoh Hiroshi

Diabetes 61 ( 8 ) 1935 - 1948 2012.08

ISSN  0012-1797

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<p>Chronic inflammation in adipose tissue contributes to obesity-related insulin resistance. The 3-phosphoinositide-dependent protein kinase 1 (Pdk1)/forkhead transcription factor (Foxo1) pathway is important in regulating glucose and energy homeostasis, but little is known about this pathway in adipose tissue macrophages (ATMs). To investigate this, we generated transgenic mice that carried macrophage/granulocyte-specific mutations, including a Pdk1 knockout (LysMPdk1 ^-/-), a Pdk1 knockout with transactivation- defective Foxo1 (Δ256LysMPdk1 ^-/-), a constitutively active nuclear (CN) Foxo1 (CNFoxo1 ^LysM), or a transactivation-defective Foxo1 (Δ256Foxo1 ^LysM). We analyzed glucose metabolism and gene expression in ATM populations isolated with fluorescence-activated cell sorting. The LysMPdk1 ^-/- mice exhibited elevated M1 macrophages in adipose tissue and insulin resistance. Overexpression of transactivation-defective Foxo1 rescued these phenotypes. CNFoxo1 ^LysM promoted transcription of the C-C motif chemokine receptor 2 (Ccr2) in ATMs and increased M1 macrophages in adipose tissue. On a high-fat diet, CNFoxo1 ^LysMmice exhibited insulin resistance. Pdk1 deletion or Foxo1 activation in bone marrow-derived macrophages abolished insulin and interleukin-4 induction of genes involved in alternative macrophage activation. Thus, Pdk1 regulated macrophage infiltration by inhibiting Foxo1-induced Ccr2 expression. This shows that the macrophage Pdk1/Foxo1 pathway is important in regulating insulin sensitivity in vivo. © 2012 by the American Diabetes Association.</p>

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Loss of Pdk1-Foxo1 signaling in myeloid cells predisposes to adipose tissue inflammation and insulin resistance

Kawano Yoshinaga, Nakae Jun, Watanabe Nobuyuki, Fujisaka Shiho, Iskandar Kristy, Sekioka Risa, Hayashi Yoshitake, Tobe Kazuyuki, Kasuga Masato, Noda Tetsuo, Yoshimura Akihiko, Onodera Masafumi, Itoh Hiroshi

Diabetes 61 ( 8 ) 1935 - 1948 2012.08

ISSN  0012-1797

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<p>Chronic inflammation in adipose tissue contributes to obesity-related insulin resistance. The 3-phosphoinositide-dependent protein kinase 1 (Pdk1)/forkhead transcription factor (Foxo1) pathway is important in regulating glucose and energy homeostasis, but little is known about this pathway in adipose tissue macrophages (ATMs). To investigate this, we generated transgenic mice that carried macrophage/granulocyte-specific mutations, including a Pdk1 knockout (LysMPdk1 ^-/-), a Pdk1 knockout with transactivation- defective Foxo1 (Δ256LysMPdk1 ^-/-), a constitutively active nuclear (CN) Foxo1 (CNFoxo1 ^LysM), or a transactivation-defective Foxo1 (Δ256Foxo1 ^LysM). We analyzed glucose metabolism and gene expression in ATM populations isolated with fluorescence-activated cell sorting. The LysMPdk1 ^-/- mice exhibited elevated M1 macrophages in adipose tissue and insulin resistance. Overexpression of transactivation-defective Foxo1 rescued these phenotypes. CNFoxo1 ^LysM promoted transcription of the C-C motif chemokine receptor 2 (Ccr2) in ATMs and increased M1 macrophages in adipose tissue. On a high-fat diet, CNFoxo1 ^LysMmice exhibited insulin resistance. Pdk1 deletion or Foxo1 activation in bone marrow-derived macrophages abolished insulin and interleukin-4 induction of genes involved in alternative macrophage activation. Thus, Pdk1 regulated macrophage infiltration by inhibiting Foxo1-induced Ccr2 expression. This shows that the macrophage Pdk1/Foxo1 pathway is important in regulating insulin sensitivity in vivo. © 2012 by the American Diabetes Association.</p>

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Dysregulation of suppressor of cytokine signaling 3 in keratinocytes causes skin inflammation mediated by interleukin-20 receptor-related cytokines

Uto-Konomi Ayako, Miyauchi Kosuke, Ozaki Naoko, Motomura Yasutaka, Suzuki Yoshie, Yoshimura Akihiko, Suzuki Shinobu, Cua Daniel, Kubo Masato

PLoS ONE 7 ( 7 )  2012.07

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<p>Homeostatic regulation of epidermal keratinocytes is controlled by the local cytokine milieu. However, a role for suppressor of cytokine signaling (SOCS), a negative feedback regulator of cytokine networks, in skin homeostasis remains unclear. Keratinocyte specific deletion of Socs3 (Socs3 cKO) caused severe skin inflammation with hyper-production of IgE, epidermal hyperplasia, and S100A8/9 expression, although Socs1 deletion caused no inflammation. The inflamed skin showed constitutive STAT3 activation and up-regulation of IL-6 and IL-20 receptor (IL-20R) related cytokines, IL-19, IL-20 and IL-24. Disease development was rescued by deletion of the Il6 gene, but not by the deletion of Il23, Il4r, or Rag1 genes. The expression of IL-6 in Socs3 cKO keratinocytes increased expression of IL-20R-related cytokines that further facilitated STAT3 hyperactivation, epidermal hyperplasia and neutrophilia. These results demonstrate that skin homeostasis is strictly regulated by the IL-6-STAT3-SOCS3 axis. Moreover, the SOCS3-mediated negative feedback loop in keratinocytes has a critical mechanistic role in the prevention of skin inflammation caused by hyperactivation of STAT3. © 2012 Uto-Konomi et al.</p>

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Dysregulation of suppressor of cytokine signaling 3 in keratinocytes causes skin inflammation mediated by interleukin-20 receptor-related cytokines

Uto-Konomi Ayako, Miyauchi Kosuke, Ozaki Naoko, Motomura Yasutaka, Suzuki Yoshie, Yoshimura Akihiko, Suzuki Shinobu, Cua Daniel, Kubo Masato

PLoS ONE 7 ( 7 )  2012.07

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<p>Homeostatic regulation of epidermal keratinocytes is controlled by the local cytokine milieu. However, a role for suppressor of cytokine signaling (SOCS), a negative feedback regulator of cytokine networks, in skin homeostasis remains unclear. Keratinocyte specific deletion of Socs3 (Socs3 cKO) caused severe skin inflammation with hyper-production of IgE, epidermal hyperplasia, and S100A8/9 expression, although Socs1 deletion caused no inflammation. The inflamed skin showed constitutive STAT3 activation and up-regulation of IL-6 and IL-20 receptor (IL-20R) related cytokines, IL-19, IL-20 and IL-24. Disease development was rescued by deletion of the Il6 gene, but not by the deletion of Il23, Il4r, or Rag1 genes. The expression of IL-6 in Socs3 cKO keratinocytes increased expression of IL-20R-related cytokines that further facilitated STAT3 hyperactivation, epidermal hyperplasia and neutrophilia. These results demonstrate that skin homeostasis is strictly regulated by the IL-6-STAT3-SOCS3 axis. Moreover, the SOCS3-mediated negative feedback loop in keratinocytes has a critical mechanistic role in the prevention of skin inflammation caused by hyperactivation of STAT3. © 2012 Uto-Konomi et al.</p>

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Forced expression of stabilized c-Fos in dendritic cells reduces cytokine production and immune responses in vivo

Yoshida Ryoko, Suzuki Mayu, Sakaguchi Ryota, Hasegawa Eiichi, Kimura Akihiro, Shichita Takashi, Sekiya Takashi, Shiraishi Hiroshi, Shimoda Kouji, Yoshimura Akihiko

Biochemical and Biophysical Research Communications 423 ( 2 ) 247 - 252 2012.06

ISSN  0006-291X

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<p>Intracellular cyclic adenosine monophosphate (cAMP) suppresses innate immunity by inhibiting proinflammatory cytokine production by monocytic cells. We have shown that the transcription factor c-Fos is responsible for cAMP-mediated suppression of inflammatory cytokine production, and that c-Fos protein is stabilized by IKKβ-mediated phosphorylation. We found that S308 is one of the major phosphorylation sites, and that the S308D mutation prolongs c-Fos halflife. To investigate the role of stabilized c-Fos protein in dendritic cells (DCs) in vivo, we generated CD11c-promoter-deriven c-FosS308D transgenic mice. As expected, bone marrow-derived DCs (BMDCs) from these Tg mice produced smaller amounts of inflammatory cytokines, including TNF-α, IL-12, and IL-23, but higher levels of IL-10, in response to LPS, than those from wild-type (Wt) mice. When T cells were co-cultured with BMDCs from Tg mice, production of Th1 and Th17 cytokines was reduced, although T cell proliferation was not affected. Tg mice demonstrated more resistance to experimental autoimmune encephalomyelitis (EAE) than did Wt mice. These data suggest that c-Fos in DCs plays a suppressive role in certain innate and adaptive immune responses. © 2012 Elsevier Inc.</p>

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Forced expression of stabilized c-Fos in dendritic cells reduces cytokine production and immune responses in vivo

Yoshida Ryoko, Suzuki Mayu, Sakaguchi Ryota, Hasegawa Eiichi, Kimura Akihiro, Shichita Takashi, Sekiya Takashi, Shiraishi Hiroshi, Shimoda Kouji, Yoshimura Akihiko

Biochemical and Biophysical Research Communications 423 ( 2 ) 247 - 252 2012.06

ISSN  0006-291X

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<p>Intracellular cyclic adenosine monophosphate (cAMP) suppresses innate immunity by inhibiting proinflammatory cytokine production by monocytic cells. We have shown that the transcription factor c-Fos is responsible for cAMP-mediated suppression of inflammatory cytokine production, and that c-Fos protein is stabilized by IKKβ-mediated phosphorylation. We found that S308 is one of the major phosphorylation sites, and that the S308D mutation prolongs c-Fos halflife. To investigate the role of stabilized c-Fos protein in dendritic cells (DCs) in vivo, we generated CD11c-promoter-deriven c-FosS308D transgenic mice. As expected, bone marrow-derived DCs (BMDCs) from these Tg mice produced smaller amounts of inflammatory cytokines, including TNF-α, IL-12, and IL-23, but higher levels of IL-10, in response to LPS, than those from wild-type (Wt) mice. When T cells were co-cultured with BMDCs from Tg mice, production of Th1 and Th17 cytokines was reduced, although T cell proliferation was not affected. Tg mice demonstrated more resistance to experimental autoimmune encephalomyelitis (EAE) than did Wt mice. These data suggest that c-Fos in DCs plays a suppressive role in certain innate and adaptive immune responses. © 2012 Elsevier Inc.</p>

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Signal-transducing adaptor protein-2 modulates fas-mediated T cell apoptosis by interacting with caspase-8

Sekine Yuichi, Yamamoto Chikako, Kakisaka Michinori, Muromoto Ryuta, Kon Shigeyuki, Ashitomi Dai, Fujita Natsuko, Yoshimura Akihiko, Oritani Kenji, Matsuda Tadashi

Journal of Immunology 188 ( 12 ) 6194 - 6204 2012.06

ISSN  0022-1767

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<p>We found that an adaptor protein, signal-transducing adaptor protein (STAP)-2, is a new member of the Fas-death-inducing signaling complex and participates in activation-induced cell death in T cells. STAP-2 enhanced Fas-mediated apoptosis and caspase-8 aggregation and activation in Jurkat T cells. Importantly, STAP-2 directly interacted with caspase-8 and Fas, resulting in enhanced interactions between caspase-8 and FADD in the Fas-death-inducing signaling complex. Moreover, STAP-2 protein has a consensus caspase-8 cleavage sequence, VEAD, in its C-terminal domain, and processing of STAP-2 by caspase-8 was crucial for Fas-induced apoptosis. Physiologic roles of STAP-2 were confirmed by observations that STAP-2-deficient mice displayed impaired activation-induced cell death and superantigen-induced T cell depletion. Therefore, STAP-2 is a novel participant in the regulation of T cell apoptosis after stimulation. Copyright © 2012 by The American Association of Immunologists, Inc.</p>

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Signal-transducing adaptor protein-2 modulates fas-mediated T cell apoptosis by interacting with caspase-8

Sekine Yuichi, Yamamoto Chikako, Kakisaka Michinori, Muromoto Ryuta, Kon Shigeyuki, Ashitomi Dai, Fujita Natsuko, Yoshimura Akihiko, Oritani Kenji, Matsuda Tadashi

Journal of Immunology 188 ( 12 ) 6194 - 6204 2012.06

ISSN  0022-1767

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<p>We found that an adaptor protein, signal-transducing adaptor protein (STAP)-2, is a new member of the Fas-death-inducing signaling complex and participates in activation-induced cell death in T cells. STAP-2 enhanced Fas-mediated apoptosis and caspase-8 aggregation and activation in Jurkat T cells. Importantly, STAP-2 directly interacted with caspase-8 and Fas, resulting in enhanced interactions between caspase-8 and FADD in the Fas-death-inducing signaling complex. Moreover, STAP-2 protein has a consensus caspase-8 cleavage sequence, VEAD, in its C-terminal domain, and processing of STAP-2 by caspase-8 was crucial for Fas-induced apoptosis. Physiologic roles of STAP-2 were confirmed by observations that STAP-2-deficient mice displayed impaired activation-induced cell death and superantigen-induced T cell depletion. Therefore, STAP-2 is a novel participant in the regulation of T cell apoptosis after stimulation. Copyright © 2012 by The American Association of Immunologists, Inc.</p>

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Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain

Shichita Takashi, Hasegawa Eiichi, Kimura Akihiro, Morita Rimpei, Sakaguchi Ryota, Takada Ichiro, Sekiya Takashi, Ooboshi Hiroaki, Kitazono Takanari, Yanagawa Toru, Ishii Tetsuro, Takahashi Hideo, Mori Shuji, Nishibori Masahiro, Kuroda Kazumichi, Akira Shizuo, Miyake Kensuke, Yoshimura Akihiko

Nature Medicine 18 ( 6 ) 911 - 917 2012.06

ISSN  1078-8956

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<p>Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. However, the mechanism that activates infiltrating macrophages in the ischemic brain remains to be clarified. Here we demonstrate that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brain cells induce expression of inflammatory cytokines including interleukin-23 in macrophages through activation of Toll-like receptor 2 (TLR2) and TLR4, thereby promoting neural cell death, even though intracellular Prxs have been shown to be neuroprotective. The extracellular release of Prxs in the ischemic core occurred 12 h after stroke onset, and neutralization of extracellular Prxs with antibodies suppressed inflammatory cytokine expression and infarct volume growth. In contrast, high mobility group box 1 (HMGB1), a well-known damage-associated molecular pattern molecule, was released before Prx and had a limited role in post-ischemic macrophage activation. We thus propose that extracellular Prxs are previously unknown danger signals in the ischemic brain and that its blocking agents are potent neuroprotective tools. © 2012 Nature America, Inc. All rights reserved.</p>

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Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain

Shichita Takashi, Hasegawa Eiichi, Kimura Akihiro, Morita Rimpei, Sakaguchi Ryota, Takada Ichiro, Sekiya Takashi, Ooboshi Hiroaki, Kitazono Takanari, Yanagawa Toru, Ishii Tetsuro, Takahashi Hideo, Mori Shuji, Nishibori Masahiro, Kuroda Kazumichi, Akira Shizuo, Miyake Kensuke, Yoshimura Akihiko

Nature Medicine 18 ( 6 ) 911 - 917 2012.06

ISSN  1078-8956

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<p>Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. However, the mechanism that activates infiltrating macrophages in the ischemic brain remains to be clarified. Here we demonstrate that peroxiredoxin (Prx) family proteins released extracellularly from necrotic brain cells induce expression of inflammatory cytokines including interleukin-23 in macrophages through activation of Toll-like receptor 2 (TLR2) and TLR4, thereby promoting neural cell death, even though intracellular Prxs have been shown to be neuroprotective. The extracellular release of Prxs in the ischemic core occurred 12 h after stroke onset, and neutralization of extracellular Prxs with antibodies suppressed inflammatory cytokine expression and infarct volume growth. In contrast, high mobility group box 1 (HMGB1), a well-known damage-associated molecular pattern molecule, was released before Prx and had a limited role in post-ischemic macrophage activation. We thus propose that extracellular Prxs are previously unknown danger signals in the ischemic brain and that its blocking agents are potent neuroprotective tools. © 2012 Nature America, Inc. All rights reserved.</p>

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Preferential induction of Th17 cells in vitro and in vivo by Fucogalactan from Ganoderma lucidum (Reishi)

Yoshida Hideyuki, Suzuki Mayu, Sakaguchi Ryota, Tani Ito, Kotani Hitoshi, Shudo Norimasa, Yoshimura Akihiko

Biochemical and Biophysical Research Communications 422 ( 1 ) 174 - 180 2012.05

ISSN  0006-291X

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<p>The mushroom known as Reishi (Ganoderma lucidum) has been used as an herbal medicine for tumor treatment and immune system activation. Because its effects on the differentiation of effector T helper cells have not yet been fully understood, we investigated the effects of Reishi and those of its principal ingredient, β-glucan, on the activation of dendritic cells and the differentiation of Th17 cells. Reishi extracts as well as purified β-glucan (Curdran) activated DCs and caused them to produce large amounts of IL-23. β-glucan also enhanced and sustained the transcription of IL-23p19. The MEK-ERK signaling pathway positively regulates IL-23p19 transcription in β-glucan-stimulated DCs. In a mixed leukocyte reaction, Reishi-stimulated DCs preferentially induced Th17 cells. Furthermore, orally-administrated Reishi increased the percentages of Th17 cells and the transcription levels of antimicrobial peptides. Our results show that Reishi and β-glucan activate DCs to produce large amounts of IL-23, which induces Th17 differentiation both in vitro and in vivo. © 2012 Elsevier Inc.</p>

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Preferential induction of Th17 cells in vitro and in vivo by Fucogalactan from Ganoderma lucidum (Reishi)

Yoshida Hideyuki, Suzuki Mayu, Sakaguchi Ryota, Tani Ito, Kotani Hitoshi, Shudo Norimasa, Yoshimura Akihiko

Biochemical and Biophysical Research Communications 422 ( 1 ) 174 - 180 2012.05

ISSN  0006-291X

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<p>The mushroom known as Reishi (Ganoderma lucidum) has been used as an herbal medicine for tumor treatment and immune system activation. Because its effects on the differentiation of effector T helper cells have not yet been fully understood, we investigated the effects of Reishi and those of its principal ingredient, β-glucan, on the activation of dendritic cells and the differentiation of Th17 cells. Reishi extracts as well as purified β-glucan (Curdran) activated DCs and caused them to produce large amounts of IL-23. β-glucan also enhanced and sustained the transcription of IL-23p19. The MEK-ERK signaling pathway positively regulates IL-23p19 transcription in β-glucan-stimulated DCs. In a mixed leukocyte reaction, Reishi-stimulated DCs preferentially induced Th17 cells. Furthermore, orally-administrated Reishi increased the percentages of Th17 cells and the transcription levels of antimicrobial peptides. Our results show that Reishi and β-glucan activate DCs to produce large amounts of IL-23, which induces Th17 differentiation both in vitro and in vivo. © 2012 Elsevier Inc.</p>

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