Papers - Yoshimura, Akihiko

CCL2-induced migration and SOCS3-mediated activation of macrophages are involved in cerulein-induced pancreatitis in mice

Saeki Keita, Kanai Takanori, Nakano Masaru, Nakamura Yuji, Miyata Naoteru, Sujino Tomohisa, Yamagishi Yoshiyuki, Ebinuma Hirotoshi, Takaishi Hiromasa, Ono Yuuichi, Takeda Kazuyoshi, Hozawa Shigenari, Yoshimura Akihiko, Hibi Toshifumi

Gastroenterology 142 ( 4 )  2012.04

ISSN  0016-5085

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<p>Background &amp; Aims: Acute pancreatitis is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with recruitment of leukocytes. We investigated the pathologic roles of innate immune cells, especially macrophages, in cerulein and L-arginineinduced acute pancreatitis in mice. Methods: Acute pancreatitis was induced by sequential peritoneal administration of cerulein to mice. We determined serum concentrations of amylase and lipase, pancreatic pathology, and features of infiltrating mononuclear cells. We performed parabiosis surgery to assess the hemodynamics of pancreatic macrophages. Results: Almost all types of immune cells, except for CD11b ^highCD11c ^- cells, were detected in the pancreas of healthy mice. However, activated CD11b ^highCD11c ^- cells, including Gr-1 ^low macrophages and Gr-1 ^high cells (granulocytes and myeloid-derived suppressor cells), were detected in damaged pancreas after cerulein administration. CCL2 ^-/- mice given cerulein injections developed significantly less severe pancreatitis, with less infiltration of CD11b ^highCD11c ^-Gr-1 ^low macrophages, but comparable infiltration of myeloid-derived suppressor cells, compared with cerulein-injected wild-type mice. Parabiosis and bone marrow analyses of these mice revealed that the CD11b ^highCD11c ^-Gr-1 ^low macrophages had moved out of the bone marrow. Furthermore, mice with macrophage-specific deletion of suppressor of cytokine signaling 3 given injections of cerulein developed less severe pancreatitis and Gr-1 ^low macrophage produced less tumor necrosis factor-α than wild-type mice given cerulein, although the absolute number of CD11b ^highCD11c ^-Gr-1 ^low macrophages was comparable between strains. Induction of acute pancreatitis by L-arginine required induction of macrophage migration by CCL2, via the receptor CCR2. Conclusions: Cerulein induction of pancreatitis in mice involves migration of CD11b ^highCD11c ^-Gr-1 ^low macrophage from the bone marrow (mediated by CCL2 via CCR2) and suppressor of cytokine signaling 3dependent activation of macrophage. These findings might lead to new therapeutic strategies for acute pancreatitis. © 2012 AGA Institute.</p>

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CCL2-induced migration and SOCS3-mediated activation of macrophages are involved in cerulein-induced pancreatitis in mice

Saeki Keita, Kanai Takanori, Nakano Masaru, Nakamura Yuji, Miyata Naoteru, Sujino Tomohisa, Yamagishi Yoshiyuki, Ebinuma Hirotoshi, Takaishi Hiromasa, Ono Yuuichi, Takeda Kazuyoshi, Hozawa Shigenari, Yoshimura Akihiko, Hibi Toshifumi

Gastroenterology 142 ( 4 )  2012.04

ISSN  0016-5085

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<p>Background &amp; Aims: Acute pancreatitis is a common inflammatory disease mediated by damage to acinar cells and subsequent pancreatic inflammation with recruitment of leukocytes. We investigated the pathologic roles of innate immune cells, especially macrophages, in cerulein and L-arginineinduced acute pancreatitis in mice. Methods: Acute pancreatitis was induced by sequential peritoneal administration of cerulein to mice. We determined serum concentrations of amylase and lipase, pancreatic pathology, and features of infiltrating mononuclear cells. We performed parabiosis surgery to assess the hemodynamics of pancreatic macrophages. Results: Almost all types of immune cells, except for CD11b ^highCD11c ^- cells, were detected in the pancreas of healthy mice. However, activated CD11b ^highCD11c ^- cells, including Gr-1 ^low macrophages and Gr-1 ^high cells (granulocytes and myeloid-derived suppressor cells), were detected in damaged pancreas after cerulein administration. CCL2 ^-/- mice given cerulein injections developed significantly less severe pancreatitis, with less infiltration of CD11b ^highCD11c ^-Gr-1 ^low macrophages, but comparable infiltration of myeloid-derived suppressor cells, compared with cerulein-injected wild-type mice. Parabiosis and bone marrow analyses of these mice revealed that the CD11b ^highCD11c ^-Gr-1 ^low macrophages had moved out of the bone marrow. Furthermore, mice with macrophage-specific deletion of suppressor of cytokine signaling 3 given injections of cerulein developed less severe pancreatitis and Gr-1 ^low macrophage produced less tumor necrosis factor-α than wild-type mice given cerulein, although the absolute number of CD11b ^highCD11c ^-Gr-1 ^low macrophages was comparable between strains. Induction of acute pancreatitis by L-arginine required induction of macrophage migration by CCL2, via the receptor CCR2. Conclusions: Cerulein induction of pancreatitis in mice involves migration of CD11b ^highCD11c ^-Gr-1 ^low macrophage from the bone marrow (mediated by CCL2 via CCR2) and suppressor of cytokine signaling 3dependent activation of macrophage. These findings might lead to new therapeutic strategies for acute pancreatitis. © 2012 AGA Institute.</p>

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JAK's SOCS

Yoshimura Akihiko, Yasukawa Hideo

Immunity 36 ( 2 ) 157 - 159 2012.02

ISSN  1074-7613

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<p>SOCS1 and SOCS3 are specific inhibitors for JAK tyrosine kinases. In this issue of Immunity, Babon et al. (2012) discovered the inhibition mechanism of SOCS3 by employing nuclear magnetic resonance and classical enzyme kinetics. © 2012 Elsevier Inc.</p>

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JAK's SOCS

Yoshimura Akihiko, Yasukawa Hideo

Immunity 36 ( 2 ) 157 - 159 2012.02

ISSN  1074-7613

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<p>SOCS1 and SOCS3 are specific inhibitors for JAK tyrosine kinases. In this issue of Immunity, Babon et al. (2012) discovered the inhibition mechanism of SOCS3 by employing nuclear magnetic resonance and classical enzyme kinetics. © 2012 Elsevier Inc.</p>

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Low dose CP-690,550 (tofacitinib), a pan-JAK inhibitor, accelerates the onset of experimental autoimmune encephalomyelitis by potentiating Th17 differentiation

Yoshida Hideyuki, Kimura Akihiro, Fukaya Tomohiro, Sekiya Takashi, Morita Rimpei, Shichita Takashi, Inoue Hiromasa, Yoshimura Akihiko

Biochemical and Biophysical Research Communications 418 ( 2 ) 234 - 240 2012.02

ISSN  0006-291X

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<p>Th17 cells, which have been implicated in autoimmune diseases, require STAT3 signaling activated by IL-6 or IL-23 for their development. Other Th1 and Th2 cytokines such as IL-2, IFN-γ and IL-4 strongly suppress Th17 development. Recently, CP-690,550 (tofacitinib), originally developed as a JAK3 inhibitor, has been shown to be effective in phase III clinical trials of rheumatoid arthritis and collagen-induced arthritis (CIA) models, but the precise mechanism of the effect, especially with respect to Th17 cells, is poorly understood. To our surprise, a low dose CP-690,550 was found to accelerate the onset of experimental autoimmune encephalomyelitis (EAE) at a concentration that suppressed CIA. At an early stage after immunization, more IL-17 production was observed in 15. mg/kg body weight CP-690,550-treated mice than in untreated mice. In vitro, CP-690,550 inhibited both Th1 and Th2 development, while promoting Th17 differentiation at 10-50. nM concentrations. Enhancement of Th17 by CP-690,550 is probably due to suppression of IL-2 signaling, because anti-IL-2 antibodies cancel the Th17-promoting effect of CP-690,550. CP-690,550 selectively inhibited IFN--induced STAT1, IL-4-induced STAT6 and IL-2-induced STAT5 at 3-30. nM, while suppression of IL-6-induced STAT3 phosphorylation required a concentration greater than 100. nM. In HEK293T cells, CP-690,550 less effectively suppressed JAK1-mediated STAT3 phosphorylation compared with JAK3. These results suggest that CP-690,550 has a different effects among JAKs and STATs, thereby affecting helper T cell differentiation, and murine autoimmune disease models. © 2012 Elsevier Inc.</p>

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Low dose CP-690,550 (tofacitinib), a pan-JAK inhibitor, accelerates the onset of experimental autoimmune encephalomyelitis by potentiating Th17 differentiation

Yoshida Hideyuki, Kimura Akihiro, Fukaya Tomohiro, Sekiya Takashi, Morita Rimpei, Shichita Takashi, Inoue Hiromasa, Yoshimura Akihiko

Biochemical and Biophysical Research Communications 418 ( 2 ) 234 - 240 2012.02

ISSN  0006-291X

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<p>Th17 cells, which have been implicated in autoimmune diseases, require STAT3 signaling activated by IL-6 or IL-23 for their development. Other Th1 and Th2 cytokines such as IL-2, IFN-γ and IL-4 strongly suppress Th17 development. Recently, CP-690,550 (tofacitinib), originally developed as a JAK3 inhibitor, has been shown to be effective in phase III clinical trials of rheumatoid arthritis and collagen-induced arthritis (CIA) models, but the precise mechanism of the effect, especially with respect to Th17 cells, is poorly understood. To our surprise, a low dose CP-690,550 was found to accelerate the onset of experimental autoimmune encephalomyelitis (EAE) at a concentration that suppressed CIA. At an early stage after immunization, more IL-17 production was observed in 15. mg/kg body weight CP-690,550-treated mice than in untreated mice. In vitro, CP-690,550 inhibited both Th1 and Th2 development, while promoting Th17 differentiation at 10-50. nM concentrations. Enhancement of Th17 by CP-690,550 is probably due to suppression of IL-2 signaling, because anti-IL-2 antibodies cancel the Th17-promoting effect of CP-690,550. CP-690,550 selectively inhibited IFN--induced STAT1, IL-4-induced STAT6 and IL-2-induced STAT5 at 3-30. nM, while suppression of IL-6-induced STAT3 phosphorylation required a concentration greater than 100. nM. In HEK293T cells, CP-690,550 less effectively suppressed JAK1-mediated STAT3 phosphorylation compared with JAK3. These results suggest that CP-690,550 has a different effects among JAKs and STATs, thereby affecting helper T cell differentiation, and murine autoimmune disease models. © 2012 Elsevier Inc.</p>

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TGFβ-activated kinase 1 (TAK1)-binding proteins (TAB) 2 and 3 negatively regulate autophagy

Takaesu Giichi, Kobayashi Takashi, Yoshimura Akihiko

Journal of Biochemistry 151 ( 2 ) 157 - 166 2012.02

ISSN  0021-924X

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<p>Transforming growth factor β-activated protein kinase 1 (TAK1)-binding protein 2 (TAB2) and its close homolog TAB3 are initially characterized as adapter proteins essential for TAK1 activation in response to interleukin-1β and tumour necrosis factor-α. However, the physiological roles of TAB2 and TAB3 are still not fully understood. Here we report that TAB2 and TAB3 bind to Beclin1 and colocalize in the cytoplasm. TAB2 also interacts with ATG13 and is phosphorylated by ULK1. Overexpression of TAB2 or TAB3 induces punctate localization of ATG5 under the normal culture condition. Knockdown of TAB2 and TAB3 results in the decrease in endogenous protein level of p62/SQSTM1 under the normal culture condition, while overexpression of TAB2 results in the accumulation of p62/SQSTM1 independently of TAK1. The decrease of p62/SQSTM1 induced by the knockdown of TAB2 and TAB3 is largely dependent on ATG5. These results suggest that TAB2 and TAB3 negatively regulate autophagy independently of TAK1 activity. © The Authors 2011. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.</p>

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TGFβ-activated kinase 1 (TAK1)-binding proteins (TAB) 2 and 3 negatively regulate autophagy

Takaesu Giichi, Kobayashi Takashi, Yoshimura Akihiko

Journal of Biochemistry 151 ( 2 ) 157 - 166 2012.02

ISSN  0021-924X

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<p>Transforming growth factor β-activated protein kinase 1 (TAK1)-binding protein 2 (TAB2) and its close homolog TAB3 are initially characterized as adapter proteins essential for TAK1 activation in response to interleukin-1β and tumour necrosis factor-α. However, the physiological roles of TAB2 and TAB3 are still not fully understood. Here we report that TAB2 and TAB3 bind to Beclin1 and colocalize in the cytoplasm. TAB2 also interacts with ATG13 and is phosphorylated by ULK1. Overexpression of TAB2 or TAB3 induces punctate localization of ATG5 under the normal culture condition. Knockdown of TAB2 and TAB3 results in the decrease in endogenous protein level of p62/SQSTM1 under the normal culture condition, while overexpression of TAB2 results in the accumulation of p62/SQSTM1 independently of TAK1. The decrease of p62/SQSTM1 induced by the knockdown of TAB2 and TAB3 is largely dependent on ATG5. These results suggest that TAB2 and TAB3 negatively regulate autophagy independently of TAK1 activity. © The Authors 2011. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.</p>

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SOCS, inflammation, and autoimmunity

Yoshimura Akihiko, Suzuki Mayu, Sakaguchi Ryota, Hanada Toshikatsu, Yasukawa Hideo

Frontiers in Immunology 3 ( MAR )  2012

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<p>Cytokines play essential roles in innate and adaptive immunity. However, excess cytokines or dysregulation of cytokine signaling will cause a variety of diseases, including allergies, autoimmune diseases, inflammation, and cancer. Most cytokines utilize the so-called Janus kinase-signal transducers and activators of transcription pathway. This pathway is negatively regulated by various mechanisms including suppressors of cytokine signaling (SOCS) proteins. SOCS proteins bind to JAK or cytokine receptors, thereby suppressing further signaling events. Especially, suppressor of cytokine signaling-1 (SOCS1) and SOCS3 are strong inhibitors of JAKs, because these two contain kinase inhibitory region at the Nterminus. Studies using conditional knockout mice have shown that SOCS proteins are key physiological as well as pathological regulators of immune homeostasis. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of helper T cell differentiation and functions. This review focuses on the roles of SOCS1 and SOCS3 in T cell mediated inflammatory diseases. © 2012 Yoshimura, Suzuki, Sakaguchi, Hanada and Yasukawa.</p>

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Smad2 and smad3 are redundantly essential for the suppression of inos synthesis in macrophages by regulating IRF3 and STAT1 pathways

Sugiyama Yuki, Kakoi Kyosuke, Kimura Akihiro, Takada Ichiro, Kashiwagi Ikko, Wakabayashi Yu, Morita Rimpei, Nomura Masatoshi, Yoshimura Akihiko

International Immunology 24 ( 4 ) 253 - 265 2012

ISSN  0953-8178

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<p>Although transforming growth factor (TGF)-β1 is a well-known immunosuppressive cytokine, little is known about the role of its downstream transcription factors, Smad2 and Smad3, in the suppression of macrophage activation. Previous studies have demonstrated that Smad3 is critical for the suppression of LPS-mediated inducible nitric oxide (NO) synthase (iNOS) induction, although the role of Smad2 remains to be investigated. In this study, we found that iNOS induction was enhanced in Smad2-deficient bone marrow-derived macrophages (BMDMs) and peritoneal macrophages in vitro and tumor-associated macrophages in vivo, compared with wild-type (WT) macrophages. However, TGF-β1 still suppressed iNOS induction in Smad2-deficient macrophages. In Smad2/3 double knockout (KO) (Smad2/3 DKO) BMDMs, LPS-mediated NO/iNOS induction was more strongly elevated than in Smad2 or Smad3 single KO BMDMs, and its suppression by exogenous TGF-β1 was severely impaired. These data suggest that Smad2 and Smad3 redundantly regulate iNOS induction. Similarly, the production of IL-6 and TNFα, but not IL-10 was augmented in Smad2/3 DKO BMDMs, suggesting that Smad2 and Smad3 also redundantly suppressed some cytokines production. In Smad2/3 DKO macrophages, TLR3- as well as TLR4-mediated IRF3 activation and IFN-β production were strongly augmented, which resulted in hyper STAT1 phosphorylation. Furthermore, IFN-β- and IFN-γ-induced iNOS induction in the absence of TLR signaling and STAT1 transcriptional activity were augmented in Smad2/3 DKO BMDMs. These results suggest that Smad2 and Smad3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway. © The Japanese Society for Immunology. 2012. All rights reserved.</p>

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Foreward

Yoshimura Akihiko

Seikagaku 84 ( 4 ) 245 2012

ISSN  0037-1017

Post-ischemic inflammation in the brain

Shichita Takashi, Sakaguchi Ryota, Suzuki Mayu, Yoshimura Akihiko

Frontiers in Immunology 3 ( MAY )  2012

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<p>Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. In this review, we focus on the post-ischemic inflammation triggered by infiltrating immune cells, macrophages, and T lymphocytes. Brain ischemia is a sterile organ, but injury-induced inflammation is mostly dependent on Toll-like receptor (TLR) 2 andTLR4. Some endogenousTLR ligands, high mobility group box 1 (HMGB1) and peroxiredoxin family proteins, in particular, are implicated in the activation and inflammatory cytokine expression in infiltrating macrophages. Following macrophage activation, T lymphocytes infiltrate the ischemic brain and regulate the delayed phase inflammation. IL17-producing γδT lymphocytes induced by IL-23 from macrophages promote ischemic brain injury, whereas regulatory T lymphocytes suppress the function of inflammatory mediators. A deeper understanding of the inflammatory mechanisms of infiltrating immune cells may lead to the development of novel neuroprotective therapies. © 2012 Shichita, Sakaguchi, Suzuki and Yoshimura.</p>

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SOCS, inflammation, and autoimmunity

Yoshimura Akihiko, Suzuki Mayu, Sakaguchi Ryota, Hanada Toshikatsu, Yasukawa Hideo

Frontiers in Immunology 3 ( MAR )  2012

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<p>Cytokines play essential roles in innate and adaptive immunity. However, excess cytokines or dysregulation of cytokine signaling will cause a variety of diseases, including allergies, autoimmune diseases, inflammation, and cancer. Most cytokines utilize the so-called Janus kinase-signal transducers and activators of transcription pathway. This pathway is negatively regulated by various mechanisms including suppressors of cytokine signaling (SOCS) proteins. SOCS proteins bind to JAK or cytokine receptors, thereby suppressing further signaling events. Especially, suppressor of cytokine signaling-1 (SOCS1) and SOCS3 are strong inhibitors of JAKs, because these two contain kinase inhibitory region at the Nterminus. Studies using conditional knockout mice have shown that SOCS proteins are key physiological as well as pathological regulators of immune homeostasis. Recent studies have also demonstrated that SOCS1 and SOCS3 are important regulators of helper T cell differentiation and functions. This review focuses on the roles of SOCS1 and SOCS3 in T cell mediated inflammatory diseases. © 2012 Yoshimura, Suzuki, Sakaguchi, Hanada and Yasukawa.</p>

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Smad2 and smad3 are redundantly essential for the suppression of inos synthesis in macrophages by regulating IRF3 and STAT1 pathways

Sugiyama Yuki, Kakoi Kyosuke, Kimura Akihiro, Takada Ichiro, Kashiwagi Ikko, Wakabayashi Yu, Morita Rimpei, Nomura Masatoshi, Yoshimura Akihiko

International Immunology 24 ( 4 ) 253 - 265 2012

ISSN  0953-8178

　View Summary

<p>Although transforming growth factor (TGF)-β1 is a well-known immunosuppressive cytokine, little is known about the role of its downstream transcription factors, Smad2 and Smad3, in the suppression of macrophage activation. Previous studies have demonstrated that Smad3 is critical for the suppression of LPS-mediated inducible nitric oxide (NO) synthase (iNOS) induction, although the role of Smad2 remains to be investigated. In this study, we found that iNOS induction was enhanced in Smad2-deficient bone marrow-derived macrophages (BMDMs) and peritoneal macrophages in vitro and tumor-associated macrophages in vivo, compared with wild-type (WT) macrophages. However, TGF-β1 still suppressed iNOS induction in Smad2-deficient macrophages. In Smad2/3 double knockout (KO) (Smad2/3 DKO) BMDMs, LPS-mediated NO/iNOS induction was more strongly elevated than in Smad2 or Smad3 single KO BMDMs, and its suppression by exogenous TGF-β1 was severely impaired. These data suggest that Smad2 and Smad3 redundantly regulate iNOS induction. Similarly, the production of IL-6 and TNFα, but not IL-10 was augmented in Smad2/3 DKO BMDMs, suggesting that Smad2 and Smad3 also redundantly suppressed some cytokines production. In Smad2/3 DKO macrophages, TLR3- as well as TLR4-mediated IRF3 activation and IFN-β production were strongly augmented, which resulted in hyper STAT1 phosphorylation. Furthermore, IFN-β- and IFN-γ-induced iNOS induction in the absence of TLR signaling and STAT1 transcriptional activity were augmented in Smad2/3 DKO BMDMs. These results suggest that Smad2 and Smad3 negatively regulate iNOS induction in macrophages by suppressing multiple steps in the IRF3-IFN-β-STAT1 pathway. © The Japanese Society for Immunology. 2012. All rights reserved.</p>

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Foreward

Yoshimura Akihiko

Seikagaku 84 ( 4 ) 245 2012

ISSN  0037-1017

Post-ischemic inflammation in the brain

Shichita Takashi, Sakaguchi Ryota, Suzuki Mayu, Yoshimura Akihiko

Frontiers in Immunology 3 ( MAY )  2012

　View Summary

<p>Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. In this review, we focus on the post-ischemic inflammation triggered by infiltrating immune cells, macrophages, and T lymphocytes. Brain ischemia is a sterile organ, but injury-induced inflammation is mostly dependent on Toll-like receptor (TLR) 2 andTLR4. Some endogenousTLR ligands, high mobility group box 1 (HMGB1) and peroxiredoxin family proteins, in particular, are implicated in the activation and inflammatory cytokine expression in infiltrating macrophages. Following macrophage activation, T lymphocytes infiltrate the ischemic brain and regulate the delayed phase inflammation. IL17-producing γδT lymphocytes induced by IL-23 from macrophages promote ischemic brain injury, whereas regulatory T lymphocytes suppress the function of inflammatory mediators. A deeper understanding of the inflammatory mechanisms of infiltrating immune cells may lead to the development of novel neuroprotective therapies. © 2012 Shichita, Sakaguchi, Suzuki and Yoshimura.</p>

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Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17

Nakagawa Ryusuke, Yoshida Hideyuki, Asakawa Mayako, Tamiya Taiga, Inoue Naoko, Morita Rimpei, Inoue Hiromasa, Nakao Atsuhito, Yoshimura Akihiko

Journal of Immunology 187 ( 9 ) 4611 - 4620 2011.11

ISSN  0022-1767

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<p>Atopic dermatitis (AD) is a common pruritic inflammatory disease triggered by a defective skin barrier and immunodysregulation. AD has been considered a typical example of a Th2 response associated with allergic disease. In the early phases of the disease, symptoms include IgE hyperproduction, eosinophil accumulation, and mast cell activation; in the chronic phase, a Th1- dominant immune response is also observed at the sites of AD skin lesions. The role of IL-17-producing Th (Th17) cells in AD has not been established. In the current study, we found that pyridone 6 (P6), a pan-JAK inhibitor, delayed the onset and reduced the magnitude of skin disease in an AD-like skin-disease model of NC/Nga mice. P6 reduced IFN-γ and IL-13, whereas it enhanced IL- 17 and IL-22 expression. In vitro, P6 also inhibited both Th1 and Th2 development, whereas it promoted Th17 differentiation from naive T cells when present within a certain range of concentrations. This was probably because P6 strongly inhibited STAT1, STAT5, and STAT6 phosphorylation, whereas STAT3 phosphorylation was less efficiently suppressed by P6 at the same concentration. Furthermore, IL-22 protects keratinocytes from apoptosis induced by IFN-γ, and administration of IL-17 and IL-22 partially ameliorated skin diseases in NC/Nga mice. These results suggested that the JAK inhibitor P6 is therapeutic for AD by modulating the balance of Th2 and Th17. Copyright © 2011 by The American Association of Immunologists, Inc.</p>

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Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17

Nakagawa Ryusuke, Yoshida Hideyuki, Asakawa Mayako, Tamiya Taiga, Inoue Naoko, Morita Rimpei, Inoue Hiromasa, Nakao Atsuhito, Yoshimura Akihiko

Journal of Immunology 187 ( 9 ) 4611 - 4620 2011.11

ISSN  0022-1767

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<p>Atopic dermatitis (AD) is a common pruritic inflammatory disease triggered by a defective skin barrier and immunodysregulation. AD has been considered a typical example of a Th2 response associated with allergic disease. In the early phases of the disease, symptoms include IgE hyperproduction, eosinophil accumulation, and mast cell activation; in the chronic phase, a Th1- dominant immune response is also observed at the sites of AD skin lesions. The role of IL-17-producing Th (Th17) cells in AD has not been established. In the current study, we found that pyridone 6 (P6), a pan-JAK inhibitor, delayed the onset and reduced the magnitude of skin disease in an AD-like skin-disease model of NC/Nga mice. P6 reduced IFN-γ and IL-13, whereas it enhanced IL- 17 and IL-22 expression. In vitro, P6 also inhibited both Th1 and Th2 development, whereas it promoted Th17 differentiation from naive T cells when present within a certain range of concentrations. This was probably because P6 strongly inhibited STAT1, STAT5, and STAT6 phosphorylation, whereas STAT3 phosphorylation was less efficiently suppressed by P6 at the same concentration. Furthermore, IL-22 protects keratinocytes from apoptosis induced by IFN-γ, and administration of IL-17 and IL-22 partially ameliorated skin diseases in NC/Nga mice. These results suggested that the JAK inhibitor P6 is therapeutic for AD by modulating the balance of Th2 and Th17. Copyright © 2011 by The American Association of Immunologists, Inc.</p>

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IL-1β and TNFα-initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis

Mori Tomoaki, Miyamoto Takeshi, Yoshida Hideyuki, Asakawa Mayoko, Kawasumi Miyuri, Kobayashi Takashi, Morioka Hideo, Chiba Kazuhiro, Toyama Yoshiaki, Yoshimura Akihiko

International Immunology 23 ( 11 ) 701 - 712 2011.11

ISSN  0953-8178

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<p>Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes irreversible joint damage and significant disability. However, the fundamental mechanisms underlying how inflammation and joint destruction in RA develop and are sustained chronically remain largely unknown. Here, we show that signal transducer and activator of transcription 3 (STAT3) is the key mediator of both chronic inflammation and joint destruction in RA. We found that inflammatory cytokines highly expressed in RA patients, such as IL-1β, tumor necrosis factor alpha and IL-6, activated STAT3 either directly or indirectly and in turn induced expression of IL-6 family cytokines, further activating STAT3 in murine osteoblastic and fibroblastic cells. STAT3 activation also induced expression of receptor activator of nuclear factor kappa B ligand (RANKL), a cytokine essential for osteoclastogenesis, and STAT3 deficiency or pharmacological inhibition promoted significant reduction in expression of both IL-6 family cytokines and RANKL in vitro. STAT3 inhibition was also effective in treating an RA model, collagen-induced arthritis, in vivo through significant reduction in expression of IL-6 family cytokines and RANKL, inhibiting both inflammation and joint destruction. Leukemia inhibitory factor expression and STAT3 activation by IL-1β were mainly promoted by IL-6 but still induced in IL-6-deficient cells. Thus, our data provide new insight into RA pathogenesis and provide evidence that inflammatory cytokines trigger a cytokine amplification loop via IL-6-STAT3 that promotes sustained inflammation and joint destruction. © The Japanese Society for Immunology. 2011. All rights reserved.</p>

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IL-1β and TNFα-initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis

Mori Tomoaki, Miyamoto Takeshi, Yoshida Hideyuki, Asakawa Mayoko, Kawasumi Miyuri, Kobayashi Takashi, Morioka Hideo, Chiba Kazuhiro, Toyama Yoshiaki, Yoshimura Akihiko

International Immunology 23 ( 11 ) 701 - 712 2011.11

ISSN  0953-8178

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<p>Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes irreversible joint damage and significant disability. However, the fundamental mechanisms underlying how inflammation and joint destruction in RA develop and are sustained chronically remain largely unknown. Here, we show that signal transducer and activator of transcription 3 (STAT3) is the key mediator of both chronic inflammation and joint destruction in RA. We found that inflammatory cytokines highly expressed in RA patients, such as IL-1β, tumor necrosis factor alpha and IL-6, activated STAT3 either directly or indirectly and in turn induced expression of IL-6 family cytokines, further activating STAT3 in murine osteoblastic and fibroblastic cells. STAT3 activation also induced expression of receptor activator of nuclear factor kappa B ligand (RANKL), a cytokine essential for osteoclastogenesis, and STAT3 deficiency or pharmacological inhibition promoted significant reduction in expression of both IL-6 family cytokines and RANKL in vitro. STAT3 inhibition was also effective in treating an RA model, collagen-induced arthritis, in vivo through significant reduction in expression of IL-6 family cytokines and RANKL, inhibiting both inflammation and joint destruction. Leukemia inhibitory factor expression and STAT3 activation by IL-1β were mainly promoted by IL-6 but still induced in IL-6-deficient cells. Thus, our data provide new insight into RA pathogenesis and provide evidence that inflammatory cytokines trigger a cytokine amplification loop via IL-6-STAT3 that promotes sustained inflammation and joint destruction. © The Japanese Society for Immunology. 2011. All rights reserved.</p>

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