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Philip Cohen - One of the best experts on this subject based on the ideXlab platform.

  • the mechanism of activation of IRAK1 and irak4 by interleukin 1 and toll like receptor agonists
    Biochemical Journal, 2017
    Co-Authors: Stefan Vollmer, Nathanael S. Gray, Sam Strickson, Tinghu Zhang, Katherine L Lee, Vikram R Rao, Philip Cohen
    Abstract:

    We have developed the first assays that measure the protein kinase activities of interleukin-1 receptor-associated kinase 1 (IRAK1) and IRAK4 reliably in human cell extracts, by employing Pellino1 as a substrate in conjunction with specific pharmacological inhibitors of IRAK1 and IRAK4. We exploited these assays to show that IRAK4 was constitutively active and that its intrinsic activity towards Pellino1 was not increased significantly by stimulation with interleukin-1 (IL-1) in IL-1R-expressing HEK293 cells, Pam3CSK4-stimulated human THP1 monocytes or primary human macrophages. Our results, in conjunction with those of other investigators, suggest that the IL-1-stimulated trans-autophosphorylation of IRAK4 is initiated by the myeloid differentiation primary response gene 88-induced dimerization of IRAK4 and is not caused by an increase in the intrinsic catalytic activity of IRAK4. In contrast with IRAK4, we found that IRAK1 was inactive in unstimulated cells and converted into an active protein kinase in response to IL-1 or Pam3CSK4 in human cells. Surprisingly, the IL-1-stimulated activation of IRAK1 was not affected by pharmacological inhibition of IRAK4 and not reversed by dephosphorylation and/or deubiquitylation, suggesting that IRAK1 catalytic activity is not triggered by a covalent modification but by an allosteric mechanism induced by its interaction with IRAK4.

  • suppression of IRAK1 or irak4 catalytic activity but not type 1 ifn signaling prevents lupus nephritis in mice expressing a ubiquitin binding defective mutant of abin1
    Journal of Immunology, 2016
    Co-Authors: Sambit Nanda, Simon J C Arthur, Francesco Marchesi, Marta Lopezpelaez, Philip Cohen
    Abstract:

    Polymorphisms in the TNIP1 gene encoding A20-binding inhibitor of NF-κB1 (ABIN1) predispose to lupus and other autoimmune diseases in at least eight human populations. We found previously that knock-in mice expressing a ubiquitin-binding–defective mutant of ABIN1 (ABIN1[D485N]) develop autoimmunity as they age and succumb to a disease resembling lupus nephritis in humans. In this article, we report that Flt3-derived dendritic cells from these mice overproduced type 1 IFNs upon stimulation with ligands that activate TLR7 or TLR9. However, crossing ABIN1[D485N] mice to IFNAR1-knockout mice that do not express the α-subunit of the type 1 IFNR did not prevent splenomegaly, the appearance of high serum levels of autoantibodies and other Igs, or liver inflammation and only reduced kidney inflammation modestly. In contrast, crossing ABIN1[D485N] mice to knock-in mice expressing catalytically inactive mutants of IRAK1 or IRAK4 prevented splenomegaly, autoimmunity, and liver and kidney inflammation. Our results support the notion that IRAK1 and/or IRAK4 are attractive targets for the development of drugs to prevent, and perhaps treat, lupus nephritis and other autoinflammatory diseases caused by the decreased ability of ABIN1 or other proteins to restrict the strength of MyD88 signaling.

  • Targeting IRAK1/IRAK4 Signaling in Waldenstrom's Macroglobulinemia
    Blood, 2015
    Co-Authors: Guang Yang, Xia Liu, Jie Chen, Nicholas Tsakmaklis, Jiaji Chen, Christopher J. Patterson, Jorge J. Castillo, Philip Cohen, Li Tan
    Abstract:

    Background: MYD88 L265P somatic mutations are highly prevalent in Waldenstrom9s macroglobulinemia (WM) (NEJM 367(9):826-33). MYD88 L265P activates multiple downstream signaling pathways including BTK and IRAK1/IRAK4 that support malignant cell growth and survival (Nature 470(7332):115-9; Blood 122(7):1222-32). Ibrutinib targets BTK, and shows high overall and major clinical response rates, though no complete responses are observed indicating alternative survival signaling. Methodology: Phospho-flow analysis of IRAK1, IRAK4, and BTK was performed in primary WM cells taken from untreated WM patients, and those on ibrutinib therapy. IRAK1 or IRAK4 knockdown experiments were performed using lentiviral shRNA transduction. Immunoprecipitation, western blot and phospho-flow studies were used to detect protein expression and phosphorylation in WM cells. Cell survival following IRAK4 or IRAK1 knockdown, ibrutinib and/or IRAK4/IRAK1 inhibitor (EMD Millipore) treatment was assessed by Annexin V staining, AlamarBlue® Cell Viability Assay or CellTiter - Glo ® Luminescent Cell Viability Assays. Results: Phospho-flow analysis of bone marrow lymphoplasmacytic cells taken from WM patients following > 6 months of continued ibrutinib treatment demonstrated highly active IRAK1 and IRAK4, but not BTK. These findings prompted us to dissect the relative impact of IRAK1 and IRAK4 in supporting WM cell survival. Using lentiviral transduction, we identified shRNAs that produced similar levels of protein reduction by western blot analysis for both IRAK1 and IRAK4. Compared to scrambled control vector, knockdown of IRAK1 or IRAK4 both produced decreased tumor cell survival in MYD88 mutated BCWM.1 and MWCL-1 cells. More pronounced apoptosis, as well as sustained reduction in tumor cell growth occurred following knockdown of IRAK1 versus IRAK4. Treatment of primary WM cells taken from untreated patients, patients on ibrutinib therapy, as well as MYD88 mutated WM cells lines with ibrutinib and a toolbox IRAK4/IRAK1 inhibitor resulted in more robust reductions in NFkB signaling, and at least additive tumor cell killing versus either agent alone. Conclusions: MYD88 L265P mutated WM cells show greater dependence on IRAK1 versus IRAK4 directed signaling. IRAK1/IRAK4 signaling may contribute to persistent WM cell survival following ibrutinib treatment. Combined BTK and IRAK inhibition leads to augmented blockade of NFKB signaling and enhanced WM cell killing. The studies provide a framework for the development and investigation of IRAK inhibitors, alone and in combination with ibrutinib in WM patients. Disclosures No relevant conflicts of interest to declare.

  • targeting IRAK1 irak4 signaling in waldenstrom s macroglobulinemia
    Blood, 2015
    Co-Authors: Guang Yang, Xia Liu, Jie Chen, Nicholas Tsakmaklis, Jiaji Chen, Christopher J. Patterson, Jorge J. Castillo, Philip Cohen, Li Tan, Sara J. Buhrlage
    Abstract:

    Background: MYD88 L265P somatic mutations are highly prevalent in Waldenstrom9s macroglobulinemia (WM) (NEJM 367(9):826-33). MYD88 L265P activates multiple downstream signaling pathways including BTK and IRAK1/IRAK4 that support malignant cell growth and survival (Nature 470(7332):115-9; Blood 122(7):1222-32). Ibrutinib targets BTK, and shows high overall and major clinical response rates, though no complete responses are observed indicating alternative survival signaling. Methodology: Phospho-flow analysis of IRAK1, IRAK4, and BTK was performed in primary WM cells taken from untreated WM patients, and those on ibrutinib therapy. IRAK1 or IRAK4 knockdown experiments were performed using lentiviral shRNA transduction. Immunoprecipitation, western blot and phospho-flow studies were used to detect protein expression and phosphorylation in WM cells. Cell survival following IRAK4 or IRAK1 knockdown, ibrutinib and/or IRAK4/IRAK1 inhibitor (EMD Millipore) treatment was assessed by Annexin V staining, AlamarBlue® Cell Viability Assay or CellTiter - Glo ® Luminescent Cell Viability Assays. Results: Phospho-flow analysis of bone marrow lymphoplasmacytic cells taken from WM patients following > 6 months of continued ibrutinib treatment demonstrated highly active IRAK1 and IRAK4, but not BTK. These findings prompted us to dissect the relative impact of IRAK1 and IRAK4 in supporting WM cell survival. Using lentiviral transduction, we identified shRNAs that produced similar levels of protein reduction by western blot analysis for both IRAK1 and IRAK4. Compared to scrambled control vector, knockdown of IRAK1 or IRAK4 both produced decreased tumor cell survival in MYD88 mutated BCWM.1 and MWCL-1 cells. More pronounced apoptosis, as well as sustained reduction in tumor cell growth occurred following knockdown of IRAK1 versus IRAK4. Treatment of primary WM cells taken from untreated patients, patients on ibrutinib therapy, as well as MYD88 mutated WM cells lines with ibrutinib and a toolbox IRAK4/IRAK1 inhibitor resulted in more robust reductions in NFkB signaling, and at least additive tumor cell killing versus either agent alone. Conclusions: MYD88 L265P mutated WM cells show greater dependence on IRAK1 versus IRAK4 directed signaling. IRAK1/IRAK4 signaling may contribute to persistent WM cell survival following ibrutinib treatment. Combined BTK and IRAK inhibition leads to augmented blockade of NFKB signaling and enhanced WM cell killing. The studies provide a framework for the development and investigation of IRAK inhibitors, alone and in combination with ibrutinib in WM patients. Disclosures No relevant conflicts of interest to declare.

  • Two Phases of Inflammatory Mediator Production Defined by the Study of IRAK2 and IRAK1 Knock-in Mice
    Journal of immunology (Baltimore Md. : 1950), 2013
    Co-Authors: Eduardo Pauls, Sambit Nanda, Hilary Smith, Rachel Toth, J. Simon C. Arthur, Philip Cohen
    Abstract:

    The roles of IL-1R–associated kinase (IRAK)2 and IRAK1 in cytokine production were investigated using immune cells from knock-in mice expressing the TNFR-associated factor 6 (TRAF6) binding-defective mutant IRAK2[E525A] or the catalytically inactive IRAK1[D359A] mutant. In bone marrow–derived macrophages (BMDMs), the IRAK2–TRAF6 interaction was required for the late (2–8 h) but not the early phase (0–2 h) of il6 and tnfa mRNA production, and hence for IL-6 and TNF-α secretion by TLR agonists that signal via MyD88. Loss of the IRAK2–TRAF6 interaction had little effect on the MyD88-dependent production of anti-inflammatory molecules produced during the early phase, such as Dual Specificity Phosphatase 1, and a modest effect on IL-10 secretion. The LPS/TLR4-stimulated production of il6 and tnfa mRNA and IL-6 and TNF-α secretion was hardly affected, because the Toll/IL-1R domain–containing adapter-inducing IFN-β (TRIF) signaling pathway was used instead of the IRAK2–TRAF6 interaction to sustain late-phase mRNA production. IRAK1 catalytic activity was not rate limiting for il6, tnfa, or il10 mRNA production or the secretion of these cytokines by BMDMs, but IFN-β mRNA induction by TLR7 and TLR9 agonists was greatly delayed in plasmacytoid dendritic cells (pDCs) from IRAK1[D359A] mice. In contrast, IFN-β mRNA production was little affected in pDCs from IRAK2[E525A] mice, but subsequent IFN-α mRNA production and IFN-α secretion were reduced. IFN-β and IFN-α production were abolished in pDCs from IRAK1[D359A] × IRAK2[E525A] double knock-in mice. Our results establish that the IRAK2–TRAF6 interaction is rate limiting for the late, but not the early phase of cytokine production in BMDM and pDCs, and that the IRAK2–TRAF6 interaction is needed to sustain IκB-inducing kinase β activity during prolonged activation of the MyD88 signaling.

Jae Youl Cho - One of the best experts on this subject based on the ideXlab platform.

  • Syk Plays a Critical Role in the Expression and Activation of IRAK1 in LPS-Treated Macrophages
    Mediators of inflammation, 2017
    Co-Authors: Jae Gwang Park, Woo Seok Yang, Jonghoon Kim, Young-jin Son, Byong Chul Yoo, Ji Hye Kim, Jae Youl Cho
    Abstract:

    To address how interleukin-1 receptor-associated kinase 1 (IRAK1) is controlled by other enzymes activated by toll-like receptor (TLR) 4, we investigated the possibility that spleen tyrosine kinase (Syk), a protein tyrosine kinase that is activated at an earlier stage during TLR4 activation, plays a central role in regulating the functional activation of IRAK1. Indeed, we found that overexpression of myeloid differentiation primary response gene 88 (MyD88), an adaptor molecule that drives TLR signaling, induced IRAK1 expression and that piceatannol, a Syk inhibitor, successfully suppressed the MyD88-dependent upregulation of IRAK1 under LPS treatment conditions. Interestingly, in Syk-knockout RAW264.7 cells, IRAK1 activity was almost completely blocked after LPS treatment, while providing a Syk-recovery gene to the knockout cells successfully restored IRAK1 expression. According to our measurements of IRAK1 mRNA levels, the transcriptional upregulation of IRAK1 was induced by LPS treatment between 4 and 60 min, and this can be suppressed in Syk knockout cells, providing an effect similar that that seen under piceatannol treatment. The overexpression of Syk reverses this effect and leads to a significantly higher IRAK1 mRNA level. Collectively, our results strongly suggest that Syk plays a critical role in regulating both the activity and transcriptional level of IRAK1.

  • thymoquinone an IRAK1 inhibitor with in vivo and in vitro anti inflammatory activities
    Scientific Reports, 2017
    Co-Authors: Muhammad Jahangir Hossen, Woo Seok Yang, Daewon Kim, Adithan Aravinthan, Jonghoon Kim, Jae Youl Cho
    Abstract:

    Thymoquinone (TQ) is a bioactive component of black seed (Nigella sativa) volatile oil and has been shown to have anti-oxidative, anti-inflammatory, and anti-cancer properties. In the present study, we explored the molecular mechanisms that underlie the anti-inflammatory effect of TQ and its target proteins using lipopolysaccharide (LPS)-stimulated murine macrophage-like RAW264.7 and human monocyte-like U937 cells, together with LPS/D-galactosamine (GalN)-induced acute hepatitis and HCl/EtOH-induced gastritis mouse models. TQ strongly inhibited the production of nitric oxide (NO) and repressed NO synthase (iNOS), tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, interleukin (IL)-6, and IL-1β expression in LPS-activated RAW264.7 cells. Treatment of LPS/D-GalN-induced hepatitis and EtOH/HCl-induced gastritis mouse models with TQ significantly ameliorated disease symptoms. Using luciferase reporter gene assays, we also showed that the nuclear levels of transcription factors and phosphorylation patterns of signaling proteins, activator protein (AP)-1, and nuclear factor (NF)-κB pathways were all affected by TQ treatment. Finally, we used additional kinase and luciferase validation assays with interleukin-1 receptor-associated kinase 1 (IRAK1) to show that IRAK1 is directly suppressed by TQ treatment. Together, these findings strongly suggest that the anti-inflammatory actions of TQ are caused by suppression of IRAK-linked AP-1/NF-κB pathways.

  • IRAK1/4-targeted anti-inflammatory action of caffeic acid.
    Mediators of inflammation, 2013
    Co-Authors: Woo Seok Yang, Deok Jeong, Jae Gwang Park, Hyo-hyun Seo, Sang Hyun Moh, Sungyoul Hong, Jae Youl Cho
    Abstract:

    Caffeic acid (CA) is a phenolic compound that is frequently present in fruits, grains, and dietary supplements. Although CA has been reported to display various biological activities such as anti-inflammatory, anti-cancer, anti-viral, and anti-oxidative effects, the action mechanism of CA is not yet fully elucidated. In this study, the anti-inflammatory action mechanism of CA was examined in lipopolysaccharide (LPS) treated macrophages (RAW264.7 cells) and HCl/EtOH-induced gastritis. CA was found to diminish nitric oxide (NO) and prostaglandin E2 (PGE2) production in LPS-stimulated RAW264.7 cells. Additionally, mRNA levels of tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, and inducible NO synthase (iNOS) were downregulated by CA. CA also strongly suppressed the nuclear translocation of AP-1 family proteins and the related upstream signaling cascade composed of interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, TGF-β-activated kinase 1 (TAK1), mitogen-activated protein kinase kinase 4/7 (MKK4/7), and c-Jun N-terminal kinase (JNK). In a direct kinase assay, CA was revealed to directly inhibit IRAK1 and IRAK4. CA also ameliorated HCl/EtOH-induced gastric symptoms via the suppression of JNK, IRAK1, and IRAK4. Therefore, our data strongly suggest that CA acts as an anti-inflammatory drug by directly suppressing IRAK1 and IRAK4.

  • IRAK1 4 targeted anti inflammatory action of caffeic acid
    Mediators of Inflammation, 2013
    Co-Authors: Woo Seok Yang, Deok Jeong, Jae Gwang Park, Hyo-hyun Seo, Sang Hyun Moh, Sungyoul Hong, Jae Youl Cho
    Abstract:

    Caffeic acid (CA) is a phenolic compound that is frequently present in fruits, grains, and dietary supplements. Although CA has been reported to display various biological activities such as anti-inflammatory, anti-cancer, anti-viral, and anti-oxidative effects, the action mechanism of CA is not yet fully elucidated. In this study, the anti-inflammatory action mechanism of CA was examined in lipopolysaccharide (LPS) treated macrophages (RAW264.7 cells) and HCl/EtOH-induced gastritis. CA was found to diminish nitric oxide (NO) and prostaglandin E2 (PGE2) production in LPS-stimulated RAW264.7 cells. Additionally, mRNA levels of tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, and inducible NO synthase (iNOS) were downregulated by CA. CA also strongly suppressed the nuclear translocation of AP-1 family proteins and the related upstream signaling cascade composed of interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, TGF-β-activated kinase 1 (TAK1), mitogen-activated protein kinase kinase 4/7 (MKK4/7), and c-Jun N-terminal kinase (JNK). In a direct kinase assay, CA was revealed to directly inhibit IRAK1 and IRAK4. CA also ameliorated HCl/EtOH-induced gastric symptoms via the suppression of JNK, IRAK1, and IRAK4. Therefore, our data strongly suggest that CA acts as an anti-inflammatory drug by directly suppressing IRAK1 and IRAK4.

  • methanol extract of osbeckia stellata suppresses lipopolysaccharide and hcl ethanol induced inflammatory responses by inhibiting src syk and IRAK1
    Journal of Ethnopharmacology, 2012
    Co-Authors: Yanyan Yang, Jae Gwang Park, Sang Hyun Moh, Sungyoul Hong, Deok Hyo Yoon, Tae Woong Kim, Seong Hwan Kim, Sukchan Lee, Jae Youl Cho
    Abstract:

    Abstract Ethnopharmacological relevance Osbeckia stellata Buch.-Ham. ex D.Don is traditionally prescribed to treat various inflammatory diseases. However, how this plant is able to modulate inflammatory responses is unknown. This study explored the anti-inflammatory effects of 99% methanol extracts of O. stellata (Os-ME). Materials and Methods The anti-inflammatory effect of Os-ME was evaluated by measuring the levels of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-treated RAW264.7 macrophage cells and by determining gastric inflammatory lesions in mice induced by HCl/ethanol (EtOH). The molecular mechanisms of the inhibitions were elucidated by analyzing the activation of transcription factors, upstream signaling cascade, and the kinase activities of target enzymes. Results Os-ME dose-dependently diminished the release of NO and PGE2, and suppressed the expression of inducible NO synthase and cyclooxygenase-2 in LPS-treated RAW264.7 cells. Os-ME clearly inhibited the translocation of c-Rel, a subunit of nuclear factor κB (NF-κB), and c-Fos, a subunit of activator protein-1 (AP-1), and their regulatory upstream enzymes including Src, Syk, and IRAK1. Interestingly, orally administered Os-ME ameliorated acute inflammatory symptoms and suppressed the activation of Src, Syk, and IKAK1 induced by HCl/EtOH treatment in mouse stomach. Conclusion Os-ME can be considered as an orally available anti-inflammatory herbal remedy with Src/Syk/NF-κB and IRAK1/AP-1 inhibitory properties.

Woo Seok Yang - One of the best experts on this subject based on the ideXlab platform.

  • Syk Plays a Critical Role in the Expression and Activation of IRAK1 in LPS-Treated Macrophages
    Mediators of inflammation, 2017
    Co-Authors: Jae Gwang Park, Woo Seok Yang, Jonghoon Kim, Young-jin Son, Byong Chul Yoo, Ji Hye Kim, Jae Youl Cho
    Abstract:

    To address how interleukin-1 receptor-associated kinase 1 (IRAK1) is controlled by other enzymes activated by toll-like receptor (TLR) 4, we investigated the possibility that spleen tyrosine kinase (Syk), a protein tyrosine kinase that is activated at an earlier stage during TLR4 activation, plays a central role in regulating the functional activation of IRAK1. Indeed, we found that overexpression of myeloid differentiation primary response gene 88 (MyD88), an adaptor molecule that drives TLR signaling, induced IRAK1 expression and that piceatannol, a Syk inhibitor, successfully suppressed the MyD88-dependent upregulation of IRAK1 under LPS treatment conditions. Interestingly, in Syk-knockout RAW264.7 cells, IRAK1 activity was almost completely blocked after LPS treatment, while providing a Syk-recovery gene to the knockout cells successfully restored IRAK1 expression. According to our measurements of IRAK1 mRNA levels, the transcriptional upregulation of IRAK1 was induced by LPS treatment between 4 and 60 min, and this can be suppressed in Syk knockout cells, providing an effect similar that that seen under piceatannol treatment. The overexpression of Syk reverses this effect and leads to a significantly higher IRAK1 mRNA level. Collectively, our results strongly suggest that Syk plays a critical role in regulating both the activity and transcriptional level of IRAK1.

  • thymoquinone an IRAK1 inhibitor with in vivo and in vitro anti inflammatory activities
    Scientific Reports, 2017
    Co-Authors: Muhammad Jahangir Hossen, Woo Seok Yang, Daewon Kim, Adithan Aravinthan, Jonghoon Kim, Jae Youl Cho
    Abstract:

    Thymoquinone (TQ) is a bioactive component of black seed (Nigella sativa) volatile oil and has been shown to have anti-oxidative, anti-inflammatory, and anti-cancer properties. In the present study, we explored the molecular mechanisms that underlie the anti-inflammatory effect of TQ and its target proteins using lipopolysaccharide (LPS)-stimulated murine macrophage-like RAW264.7 and human monocyte-like U937 cells, together with LPS/D-galactosamine (GalN)-induced acute hepatitis and HCl/EtOH-induced gastritis mouse models. TQ strongly inhibited the production of nitric oxide (NO) and repressed NO synthase (iNOS), tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, interleukin (IL)-6, and IL-1β expression in LPS-activated RAW264.7 cells. Treatment of LPS/D-GalN-induced hepatitis and EtOH/HCl-induced gastritis mouse models with TQ significantly ameliorated disease symptoms. Using luciferase reporter gene assays, we also showed that the nuclear levels of transcription factors and phosphorylation patterns of signaling proteins, activator protein (AP)-1, and nuclear factor (NF)-κB pathways were all affected by TQ treatment. Finally, we used additional kinase and luciferase validation assays with interleukin-1 receptor-associated kinase 1 (IRAK1) to show that IRAK1 is directly suppressed by TQ treatment. Together, these findings strongly suggest that the anti-inflammatory actions of TQ are caused by suppression of IRAK-linked AP-1/NF-κB pathways.

  • the dietary flavonoid kaempferol mediates anti inflammatory responses via the src syk IRAK1 and irak4 molecular targets
    Mediators of Inflammation, 2015
    Co-Authors: Shi Hyoung Kim, Woo Seok Yang, Jae Gwang Park, Jongsung Lee, Gye Won Park, Han Gyung Kim, Kwangsoo Baek, Nak Yoon Sung, Muhammad Jahangir Hossen, Minam Lee
    Abstract:

    Even though a lot of reports have suggested the anti-inflammatory activity of kaempferol (KF) in macrophages, little is known about its exact anti-inflammatory mode of action and its immunopharmacological target molecules. In this study, we explored anti-inflammatory activity of KF in LPS-treated macrophages. In particular, molecular targets for KF action were identified by using biochemical and molecular biological analyses. KF suppressed the release of nitric oxide (NO) and prostaglandin E2 (PGE2), downregulated the cellular adhesion of U937 cells to fibronectin (FN), neutralized the generation of radicals, and diminished mRNA expression levels of inflammatory genes encoding inducible NO synthase (iNOS), TNF-α, and cyclooxygenase- (COX-) 2 in lipopolysaccharide- (LPS-) and sodium nitroprusside- (SNP-) treated RAW264.7 cells and peritoneal macrophages. KF reduced NF-κB (p65 and p50) and AP-1 (c-Jun and c-Fos) levels in the nucleus and their transcriptional activity. Interestingly, it was found that Src, Syk, IRAK1, and IRAK4 responsible for NF-κB and AP-1 activation were identified as the direct molecular targets of KF by kinase enzyme assays and by measuring their phosphorylation patterns. KF was revealed to have in vitro and in vivo anti-inflammatory activity by the direct suppression of Src, Syk, IRAK1, and IRAK4, involved in the activation of NF-κB and AP-1.

  • IRAK1/4-targeted anti-inflammatory action of caffeic acid.
    Mediators of inflammation, 2013
    Co-Authors: Woo Seok Yang, Deok Jeong, Jae Gwang Park, Hyo-hyun Seo, Sang Hyun Moh, Sungyoul Hong, Jae Youl Cho
    Abstract:

    Caffeic acid (CA) is a phenolic compound that is frequently present in fruits, grains, and dietary supplements. Although CA has been reported to display various biological activities such as anti-inflammatory, anti-cancer, anti-viral, and anti-oxidative effects, the action mechanism of CA is not yet fully elucidated. In this study, the anti-inflammatory action mechanism of CA was examined in lipopolysaccharide (LPS) treated macrophages (RAW264.7 cells) and HCl/EtOH-induced gastritis. CA was found to diminish nitric oxide (NO) and prostaglandin E2 (PGE2) production in LPS-stimulated RAW264.7 cells. Additionally, mRNA levels of tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, and inducible NO synthase (iNOS) were downregulated by CA. CA also strongly suppressed the nuclear translocation of AP-1 family proteins and the related upstream signaling cascade composed of interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, TGF-β-activated kinase 1 (TAK1), mitogen-activated protein kinase kinase 4/7 (MKK4/7), and c-Jun N-terminal kinase (JNK). In a direct kinase assay, CA was revealed to directly inhibit IRAK1 and IRAK4. CA also ameliorated HCl/EtOH-induced gastric symptoms via the suppression of JNK, IRAK1, and IRAK4. Therefore, our data strongly suggest that CA acts as an anti-inflammatory drug by directly suppressing IRAK1 and IRAK4.

  • IRAK1 4 targeted anti inflammatory action of caffeic acid
    Mediators of Inflammation, 2013
    Co-Authors: Woo Seok Yang, Deok Jeong, Jae Gwang Park, Hyo-hyun Seo, Sang Hyun Moh, Sungyoul Hong, Jae Youl Cho
    Abstract:

    Caffeic acid (CA) is a phenolic compound that is frequently present in fruits, grains, and dietary supplements. Although CA has been reported to display various biological activities such as anti-inflammatory, anti-cancer, anti-viral, and anti-oxidative effects, the action mechanism of CA is not yet fully elucidated. In this study, the anti-inflammatory action mechanism of CA was examined in lipopolysaccharide (LPS) treated macrophages (RAW264.7 cells) and HCl/EtOH-induced gastritis. CA was found to diminish nitric oxide (NO) and prostaglandin E2 (PGE2) production in LPS-stimulated RAW264.7 cells. Additionally, mRNA levels of tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, and inducible NO synthase (iNOS) were downregulated by CA. CA also strongly suppressed the nuclear translocation of AP-1 family proteins and the related upstream signaling cascade composed of interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, TGF-β-activated kinase 1 (TAK1), mitogen-activated protein kinase kinase 4/7 (MKK4/7), and c-Jun N-terminal kinase (JNK). In a direct kinase assay, CA was revealed to directly inhibit IRAK1 and IRAK4. CA also ameliorated HCl/EtOH-induced gastric symptoms via the suppression of JNK, IRAK1, and IRAK4. Therefore, our data strongly suggest that CA acts as an anti-inflammatory drug by directly suppressing IRAK1 and IRAK4.

Jae Gwang Park - One of the best experts on this subject based on the ideXlab platform.

  • Syk Plays a Critical Role in the Expression and Activation of IRAK1 in LPS-Treated Macrophages
    Mediators of inflammation, 2017
    Co-Authors: Jae Gwang Park, Woo Seok Yang, Jonghoon Kim, Young-jin Son, Byong Chul Yoo, Ji Hye Kim, Jae Youl Cho
    Abstract:

    To address how interleukin-1 receptor-associated kinase 1 (IRAK1) is controlled by other enzymes activated by toll-like receptor (TLR) 4, we investigated the possibility that spleen tyrosine kinase (Syk), a protein tyrosine kinase that is activated at an earlier stage during TLR4 activation, plays a central role in regulating the functional activation of IRAK1. Indeed, we found that overexpression of myeloid differentiation primary response gene 88 (MyD88), an adaptor molecule that drives TLR signaling, induced IRAK1 expression and that piceatannol, a Syk inhibitor, successfully suppressed the MyD88-dependent upregulation of IRAK1 under LPS treatment conditions. Interestingly, in Syk-knockout RAW264.7 cells, IRAK1 activity was almost completely blocked after LPS treatment, while providing a Syk-recovery gene to the knockout cells successfully restored IRAK1 expression. According to our measurements of IRAK1 mRNA levels, the transcriptional upregulation of IRAK1 was induced by LPS treatment between 4 and 60 min, and this can be suppressed in Syk knockout cells, providing an effect similar that that seen under piceatannol treatment. The overexpression of Syk reverses this effect and leads to a significantly higher IRAK1 mRNA level. Collectively, our results strongly suggest that Syk plays a critical role in regulating both the activity and transcriptional level of IRAK1.

  • the dietary flavonoid kaempferol mediates anti inflammatory responses via the src syk IRAK1 and irak4 molecular targets
    Mediators of Inflammation, 2015
    Co-Authors: Shi Hyoung Kim, Woo Seok Yang, Jae Gwang Park, Jongsung Lee, Gye Won Park, Han Gyung Kim, Kwangsoo Baek, Nak Yoon Sung, Muhammad Jahangir Hossen, Minam Lee
    Abstract:

    Even though a lot of reports have suggested the anti-inflammatory activity of kaempferol (KF) in macrophages, little is known about its exact anti-inflammatory mode of action and its immunopharmacological target molecules. In this study, we explored anti-inflammatory activity of KF in LPS-treated macrophages. In particular, molecular targets for KF action were identified by using biochemical and molecular biological analyses. KF suppressed the release of nitric oxide (NO) and prostaglandin E2 (PGE2), downregulated the cellular adhesion of U937 cells to fibronectin (FN), neutralized the generation of radicals, and diminished mRNA expression levels of inflammatory genes encoding inducible NO synthase (iNOS), TNF-α, and cyclooxygenase- (COX-) 2 in lipopolysaccharide- (LPS-) and sodium nitroprusside- (SNP-) treated RAW264.7 cells and peritoneal macrophages. KF reduced NF-κB (p65 and p50) and AP-1 (c-Jun and c-Fos) levels in the nucleus and their transcriptional activity. Interestingly, it was found that Src, Syk, IRAK1, and IRAK4 responsible for NF-κB and AP-1 activation were identified as the direct molecular targets of KF by kinase enzyme assays and by measuring their phosphorylation patterns. KF was revealed to have in vitro and in vivo anti-inflammatory activity by the direct suppression of Src, Syk, IRAK1, and IRAK4, involved in the activation of NF-κB and AP-1.

  • IRAK1/4-targeted anti-inflammatory action of caffeic acid.
    Mediators of inflammation, 2013
    Co-Authors: Woo Seok Yang, Deok Jeong, Jae Gwang Park, Hyo-hyun Seo, Sang Hyun Moh, Sungyoul Hong, Jae Youl Cho
    Abstract:

    Caffeic acid (CA) is a phenolic compound that is frequently present in fruits, grains, and dietary supplements. Although CA has been reported to display various biological activities such as anti-inflammatory, anti-cancer, anti-viral, and anti-oxidative effects, the action mechanism of CA is not yet fully elucidated. In this study, the anti-inflammatory action mechanism of CA was examined in lipopolysaccharide (LPS) treated macrophages (RAW264.7 cells) and HCl/EtOH-induced gastritis. CA was found to diminish nitric oxide (NO) and prostaglandin E2 (PGE2) production in LPS-stimulated RAW264.7 cells. Additionally, mRNA levels of tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, and inducible NO synthase (iNOS) were downregulated by CA. CA also strongly suppressed the nuclear translocation of AP-1 family proteins and the related upstream signaling cascade composed of interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, TGF-β-activated kinase 1 (TAK1), mitogen-activated protein kinase kinase 4/7 (MKK4/7), and c-Jun N-terminal kinase (JNK). In a direct kinase assay, CA was revealed to directly inhibit IRAK1 and IRAK4. CA also ameliorated HCl/EtOH-induced gastric symptoms via the suppression of JNK, IRAK1, and IRAK4. Therefore, our data strongly suggest that CA acts as an anti-inflammatory drug by directly suppressing IRAK1 and IRAK4.

  • IRAK1 4 targeted anti inflammatory action of caffeic acid
    Mediators of Inflammation, 2013
    Co-Authors: Woo Seok Yang, Deok Jeong, Jae Gwang Park, Hyo-hyun Seo, Sang Hyun Moh, Sungyoul Hong, Jae Youl Cho
    Abstract:

    Caffeic acid (CA) is a phenolic compound that is frequently present in fruits, grains, and dietary supplements. Although CA has been reported to display various biological activities such as anti-inflammatory, anti-cancer, anti-viral, and anti-oxidative effects, the action mechanism of CA is not yet fully elucidated. In this study, the anti-inflammatory action mechanism of CA was examined in lipopolysaccharide (LPS) treated macrophages (RAW264.7 cells) and HCl/EtOH-induced gastritis. CA was found to diminish nitric oxide (NO) and prostaglandin E2 (PGE2) production in LPS-stimulated RAW264.7 cells. Additionally, mRNA levels of tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, and inducible NO synthase (iNOS) were downregulated by CA. CA also strongly suppressed the nuclear translocation of AP-1 family proteins and the related upstream signaling cascade composed of interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, TGF-β-activated kinase 1 (TAK1), mitogen-activated protein kinase kinase 4/7 (MKK4/7), and c-Jun N-terminal kinase (JNK). In a direct kinase assay, CA was revealed to directly inhibit IRAK1 and IRAK4. CA also ameliorated HCl/EtOH-induced gastric symptoms via the suppression of JNK, IRAK1, and IRAK4. Therefore, our data strongly suggest that CA acts as an anti-inflammatory drug by directly suppressing IRAK1 and IRAK4.

  • methanol extract of osbeckia stellata suppresses lipopolysaccharide and hcl ethanol induced inflammatory responses by inhibiting src syk and IRAK1
    Journal of Ethnopharmacology, 2012
    Co-Authors: Yanyan Yang, Jae Gwang Park, Sang Hyun Moh, Sungyoul Hong, Deok Hyo Yoon, Tae Woong Kim, Seong Hwan Kim, Sukchan Lee, Jae Youl Cho
    Abstract:

    Abstract Ethnopharmacological relevance Osbeckia stellata Buch.-Ham. ex D.Don is traditionally prescribed to treat various inflammatory diseases. However, how this plant is able to modulate inflammatory responses is unknown. This study explored the anti-inflammatory effects of 99% methanol extracts of O. stellata (Os-ME). Materials and Methods The anti-inflammatory effect of Os-ME was evaluated by measuring the levels of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-treated RAW264.7 macrophage cells and by determining gastric inflammatory lesions in mice induced by HCl/ethanol (EtOH). The molecular mechanisms of the inhibitions were elucidated by analyzing the activation of transcription factors, upstream signaling cascade, and the kinase activities of target enzymes. Results Os-ME dose-dependently diminished the release of NO and PGE2, and suppressed the expression of inducible NO synthase and cyclooxygenase-2 in LPS-treated RAW264.7 cells. Os-ME clearly inhibited the translocation of c-Rel, a subunit of nuclear factor κB (NF-κB), and c-Fos, a subunit of activator protein-1 (AP-1), and their regulatory upstream enzymes including Src, Syk, and IRAK1. Interestingly, orally administered Os-ME ameliorated acute inflammatory symptoms and suppressed the activation of Src, Syk, and IKAK1 induced by HCl/EtOH treatment in mouse stomach. Conclusion Os-ME can be considered as an orally available anti-inflammatory herbal remedy with Src/Syk/NF-κB and IRAK1/AP-1 inhibitory properties.

Sungyoul Hong - One of the best experts on this subject based on the ideXlab platform.

  • IRAK1/4-targeted anti-inflammatory action of caffeic acid.
    Mediators of inflammation, 2013
    Co-Authors: Woo Seok Yang, Deok Jeong, Jae Gwang Park, Hyo-hyun Seo, Sang Hyun Moh, Sungyoul Hong, Jae Youl Cho
    Abstract:

    Caffeic acid (CA) is a phenolic compound that is frequently present in fruits, grains, and dietary supplements. Although CA has been reported to display various biological activities such as anti-inflammatory, anti-cancer, anti-viral, and anti-oxidative effects, the action mechanism of CA is not yet fully elucidated. In this study, the anti-inflammatory action mechanism of CA was examined in lipopolysaccharide (LPS) treated macrophages (RAW264.7 cells) and HCl/EtOH-induced gastritis. CA was found to diminish nitric oxide (NO) and prostaglandin E2 (PGE2) production in LPS-stimulated RAW264.7 cells. Additionally, mRNA levels of tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, and inducible NO synthase (iNOS) were downregulated by CA. CA also strongly suppressed the nuclear translocation of AP-1 family proteins and the related upstream signaling cascade composed of interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, TGF-β-activated kinase 1 (TAK1), mitogen-activated protein kinase kinase 4/7 (MKK4/7), and c-Jun N-terminal kinase (JNK). In a direct kinase assay, CA was revealed to directly inhibit IRAK1 and IRAK4. CA also ameliorated HCl/EtOH-induced gastric symptoms via the suppression of JNK, IRAK1, and IRAK4. Therefore, our data strongly suggest that CA acts as an anti-inflammatory drug by directly suppressing IRAK1 and IRAK4.

  • IRAK1 4 targeted anti inflammatory action of caffeic acid
    Mediators of Inflammation, 2013
    Co-Authors: Woo Seok Yang, Deok Jeong, Jae Gwang Park, Hyo-hyun Seo, Sang Hyun Moh, Sungyoul Hong, Jae Youl Cho
    Abstract:

    Caffeic acid (CA) is a phenolic compound that is frequently present in fruits, grains, and dietary supplements. Although CA has been reported to display various biological activities such as anti-inflammatory, anti-cancer, anti-viral, and anti-oxidative effects, the action mechanism of CA is not yet fully elucidated. In this study, the anti-inflammatory action mechanism of CA was examined in lipopolysaccharide (LPS) treated macrophages (RAW264.7 cells) and HCl/EtOH-induced gastritis. CA was found to diminish nitric oxide (NO) and prostaglandin E2 (PGE2) production in LPS-stimulated RAW264.7 cells. Additionally, mRNA levels of tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, and inducible NO synthase (iNOS) were downregulated by CA. CA also strongly suppressed the nuclear translocation of AP-1 family proteins and the related upstream signaling cascade composed of interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, TGF-β-activated kinase 1 (TAK1), mitogen-activated protein kinase kinase 4/7 (MKK4/7), and c-Jun N-terminal kinase (JNK). In a direct kinase assay, CA was revealed to directly inhibit IRAK1 and IRAK4. CA also ameliorated HCl/EtOH-induced gastric symptoms via the suppression of JNK, IRAK1, and IRAK4. Therefore, our data strongly suggest that CA acts as an anti-inflammatory drug by directly suppressing IRAK1 and IRAK4.

  • methanol extract of osbeckia stellata suppresses lipopolysaccharide and hcl ethanol induced inflammatory responses by inhibiting src syk and IRAK1
    Journal of Ethnopharmacology, 2012
    Co-Authors: Yanyan Yang, Jae Gwang Park, Sang Hyun Moh, Sungyoul Hong, Deok Hyo Yoon, Tae Woong Kim, Seong Hwan Kim, Sukchan Lee, Jae Youl Cho
    Abstract:

    Abstract Ethnopharmacological relevance Osbeckia stellata Buch.-Ham. ex D.Don is traditionally prescribed to treat various inflammatory diseases. However, how this plant is able to modulate inflammatory responses is unknown. This study explored the anti-inflammatory effects of 99% methanol extracts of O. stellata (Os-ME). Materials and Methods The anti-inflammatory effect of Os-ME was evaluated by measuring the levels of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-treated RAW264.7 macrophage cells and by determining gastric inflammatory lesions in mice induced by HCl/ethanol (EtOH). The molecular mechanisms of the inhibitions were elucidated by analyzing the activation of transcription factors, upstream signaling cascade, and the kinase activities of target enzymes. Results Os-ME dose-dependently diminished the release of NO and PGE2, and suppressed the expression of inducible NO synthase and cyclooxygenase-2 in LPS-treated RAW264.7 cells. Os-ME clearly inhibited the translocation of c-Rel, a subunit of nuclear factor κB (NF-κB), and c-Fos, a subunit of activator protein-1 (AP-1), and their regulatory upstream enzymes including Src, Syk, and IRAK1. Interestingly, orally administered Os-ME ameliorated acute inflammatory symptoms and suppressed the activation of Src, Syk, and IKAK1 induced by HCl/EtOH treatment in mouse stomach. Conclusion Os-ME can be considered as an orally available anti-inflammatory herbal remedy with Src/Syk/NF-κB and IRAK1/AP-1 inhibitory properties.