The critical role of kinase activity of interleukin-1 receptor-associated kinase 4 in animal models of joint inflammation

2009 ◽  
Vol 60 (6) ◽  
pp. 1661-1671 ◽  
Author(s):  
Magdalena Koziczak-Holbro ◽  
Amanda Littlewood-Evans ◽  
Bernadette Pöllinger ◽  
Jiri Kovarik ◽  
Janet Dawson ◽  
...  
Keyword(s):  
Animal Models ◽  
Kinase Activity ◽  
Interleukin 1 ◽  
Critical Role ◽  
Joint Inflammation

scholarly journals Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor–mediated immune responses but not in TCR signaling

2007 ◽  
Vol 204 (5) ◽  
pp. 1013-1024 ◽  
Author(s):  
Tatsukata Kawagoe ◽  
Shintaro Sato ◽  
Andreas Jung ◽  
Masahiro Yamamoto ◽  
Kosuke Matsui ◽  
...  
Keyword(s):  
Immune Responses ◽  
Kinase Activity ◽  
Interleukin 1 ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Toll Like Receptor ◽  
Tcr Signaling ◽  
Mitogen Activated Protein

Interleukin-1 receptor–associated kinase 4 (IRAK-4) was reported to be essential for the Toll-like receptor (TLR)– and T cell receptor (TCR)–mediated signaling leading to the activation of nuclear factor κB (NF-κB). However, the importance of kinase activity of IRAK family members is unclear. In this study, we investigated the functional role of IRAK-4 activity in vivo by generating mice carrying a knockin mutation (KK213AA) that abrogates its kinase activity. IRAK-4KN/KN mice were highly resistant to TLR-induced shock response. The cytokine production in response to TLR ligands was severely impaired in IRAK-4KN/KN as well as IRAK-4−/− macrophages. The IRAK-4 activity was essential for the activation of signaling pathways leading to mitogen-activated protein kinases. TLR-induced IRAK-4/IRAK-1–dependent and –independent pathways were involved in early induction of NF-κB–regulated genes in response to TLR ligands such as tumor necrosis factor α and IκBζ. In contrast to a previous paper (Suzuki, N., S. Suzuki, D.G. Millar, M. Unno, H. Hara, T. Calzascia, S. Yamasaki, T. Yokosuka, N.J. Chen, A.R. Elford, et al. 2006. Science. 311:1927–1932), the TCR signaling was not impaired in IRAK-4−/− and IRAK-4KN/KN mice. Thus, the kinase activity of IRAK-4 is essential for the regulation of TLR-mediated innate immune responses.

scholarly journals Role of Cathepsin S in Periodontal Inflammation and Infection

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
S. Memmert ◽  
A. Damanaki ◽  
A. V. B. Nogueira ◽  
S. Eick ◽  
M. Nokhbehsaim ◽  
...  
Keyword(s):  
Periodontal Diseases ◽  
Interleukin 1 ◽  
Critical Role ◽  
Gingival Tissue ◽  
Cathepsin S ◽  
Protein Levels ◽  
Periodontal Inflammation

Cathepsin S is a cysteine protease and regulator of autophagy with possible involvement in periodontitis. The objective of this study was to investigate whether cathepsin S is involved in the pathogenesis of periodontal diseases. Human periodontal fibroblasts were cultured under inflammatory and infectious conditions elicited by interleukin-1β and Fusobacterium nucleatum, respectively. An array-based approach was used to analyze differential expression of autophagy-associated genes. Cathepsin S was upregulated most strongly and thus further studied in vitro at gene and protein levels. In vivo, gingival tissue biopsies from rats with ligature-induced periodontitis and from periodontitis patients were also analyzed at transcriptional and protein levels. Multiple gene expression changes due to interleukin-1β and F. nucleatum were observed in vitro. Both stimulants caused a significant cathepsin S upregulation. A significantly elevated cathepsin S expression in gingival biopsies from rats with experimental periodontitis was found in vivo, as compared to that from control. Gingival biopsies from periodontitis patients showed a significantly higher cathepsin S expression than those from healthy gingiva. Our findings provide original evidence that cathepsin S is increased in periodontal cells and tissues under inflammatory and infectious conditions, suggesting a critical role of this autophagy-associated molecule in the pathogenesis of periodontitis.

scholarly journals Differential attenuation of β2 integrin–dependent and –independent neutrophil migration by Ly6G ligation

2019 ◽  
Vol 3 (3) ◽  
pp. 256-267 ◽  
Author(s):  
Pierre Cunin ◽  
Pui Y. Lee ◽  
Edy Kim ◽  
Angela B. Schmider ◽  
Nathalie Cloutier ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Neutrophil Migration ◽  
Surface Protein ◽  
Joint Inflammation ◽  
Selective Inhibition ◽  
Β2 Integrin ◽  
Β2 Integrins ◽  
Neutrophil Surface

Abstract Antibody ligation of the murine neutrophil surface protein Ly6G disrupts neutrophil migration in some contexts but not others. We tested whether this variability reflected divergent dependence of neutrophil migration on β2 integrins, adhesion molecules that interact with Ly6G at the neutrophil surface. In integrin-dependent murine arthritis, Ly6G ligation attenuated joint inflammation, even though mice lacking Ly6G altogether developed arthritis normally. By contrast, Ly6G ligation had no impact on integrin-independent neutrophil migration into inflamed lung. In peritoneum, the role of β2 integrins varied with stimulus, proving dispensable for neutrophil entry in Escherichia coli peritonitis but contributory in interleukin 1 (IL-1)–mediated sterile peritonitis. Correspondingly, Ly6G ligation attenuated only IL-1 peritonitis, disrupting the molecular association between integrins and Ly6G and inducing cell-intrinsic blockade restricted to integrin-dependent migration. Consistent with this observation, Ly6G ligation impaired integrin-mediated postadhesion strengthening for neutrophils arresting on activated cremaster endothelium in vivo. Together, these findings identify selective inhibition of integrin-mediated neutrophil emigration through Ly6G ligation, highlighting the marked site and stimulus specificity of β2 integrin dependence in neutrophil migration.

scholarly journals A critical role for IRAK4 kinase activity in Toll-like receptor–mediated innate immunity

2007 ◽  
Vol 204 (5) ◽  
pp. 1025-1036 ◽  
Author(s):  
Tae Whan Kim ◽  
Kirk Staschke ◽  
Katarzyna Bulek ◽  
Jianhong Yao ◽  
Kristi Peters ◽  
...  
Keyword(s):  
Immune Responses ◽  
Kinase Activity ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Type I ◽  
Toll Like Receptor ◽  
Chemokine Production ◽  
Cytokines And Chemokines ◽  
Plasmacytoid Dcs

IRAK4 is a member of IL-1 receptor (IL-1R)–associated kinase (IRAK) family and has been shown to play an essential role in Toll-like receptor (TLR)–mediated signaling. We recently generated IRAK4 kinase-inactive knock-in mice to examine the role of kinase activity of IRAK4 in TLR-mediated signaling pathways. The IRAK4 kinase–inactive knock-in mice were completely resistant to lipopolysaccharide (LPS)- and CpG-induced shock, due to impaired TLR-mediated induction of proinflammatory cytokines and chemokines. Although inactivation of IRAK4 kinase activity did not affect the levels of TLR/IL-1R–mediated nuclear factor κB activation, a reduction of LPS-, R848-, and IL-1–mediated mRNA stability contributed to the reduced cytokine and chemokine production in bone marrow–derived macrophages from IRAK4 kinase–inactive knock-in mice. Both TLR7- and TLR9-mediated type I interferon production was abolished in plasmacytoid dendritic cells isolated from IRAK4 knock-in mice. In addition, influenza virus–induced production of interferons in plasmacytoid DCs was also dependent on IRAK4 kinase activity. Collectively, our results indicate that IRAK4 kinase activity plays a critical role in TLR-dependent immune responses.

scholarly journals Critical role of kinase activity of hematopoietic progenitor kinase 1 in anti-tumor immune surveillance

PLoS ONE ◽  
2019 ◽  
Vol 14 (3) ◽  
pp. e0212670 ◽  
Author(s):  
Jinqi Liu ◽  
Joshua Curtin ◽  
Dan You ◽  
Stephen Hillerman ◽  
Bifang Li-Wang ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Critical Role ◽  
Immune Surveillance ◽  
Hematopoietic Progenitor

scholarly journals Role of Interleukin- (IL-) 17 in the Pathogenesis and Targeted Therapies in Spondyloarthropathies

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
I-Tsu Chyuan ◽  
Ji-Yih Chen
Keyword(s):  
Animal Studies ◽  
Association Studies ◽  
Critical Role ◽  
Genetic Association Studies ◽  
Joint Inflammation ◽  
New Bone Formation ◽  
Unique Type ◽  
Targeting Therapy ◽  
Bone Damage

Spondyloarthropathy (SpA) is a unique type of joint inflammation characterized by coexisting erosive bone damage and pathological new bone formation. Previous genetic association studies have demonstrated that several cytokine pathways play a critical role in the pathogenesis of ankylosing spondylitis (AS), psoriatic arthritis (PsA), and other types of SpA. In addition to several well-known proinflammatory cytokines, recent studies suggest that IL-17 plays a pivotal role in the pathogenesis of SpA. Further evidence from human and animal studies have defined that IL-17 and IL-17-producing cells contribute to tissue inflammation, autoimmunity, and host defense, leading to the following pathologic events associated with SpA. Recently, several clinical trials targeting IL-17 pathways demonstrated the positive response of IL-17 blockade in treating AS, indicating a great potential of IL-17-targeting therapy in SpA. In this review article, we have discussed the contributing role of IL-17 and different IL-17-producing cells in the pathogenesis of SpA and provided an outline of therapeutic application of the IL-17 blockade in the treatment of SpA. Other targeted cytokines associated with IL-17 axis in SpA will also be included.

scholarly journals Phosphoproteome-based kinase activity profiling reveals the critical role of MAP2K2 and PLK1 in neuronal autophagy

Autophagy ◽  
2017 ◽  
Vol 13 (11) ◽  
pp. 1969-1980 ◽  
Author(s):  
Lei-Lei Chen ◽  
Yong-Bo Wang ◽  
Ju-Xian Song ◽  
Wan-Kun Deng ◽  
Jia-Hong Lu ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Critical Role ◽  
Activity Profiling ◽  
Neuronal Autophagy

Critical role of interleukin 1 for the initiation and resolution of pulmonary inflammation induced by carbon nanomaterials

2014 ◽  
Vol 229 ◽  
pp. S192-S193
Author(s):  
Nunja C. Habel ◽  
David Kutschke ◽  
Oliver Eickelberg ◽  
Silke Meiners ◽  
Tobias Stoeger
Keyword(s):  
Carbon Nanomaterials ◽  
Interleukin 1 ◽  
Pulmonary Inflammation ◽  
Critical Role

scholarly journals Role for polo-like kinase 4 in mediation of cytokinesis

2019 ◽  
Vol 116 (23) ◽  
pp. 11309-11318 ◽  
Author(s):  
Michael F. Press ◽  
Bin Xie ◽  
Simon Davenport ◽  
Yu Zhou ◽  
Roberta Guzman ◽  
...  
Keyword(s):  
Cell Division ◽  
Kinase Activity ◽  
Critical Role ◽  
Mitotic Catastrophe ◽  
Centrosome Duplication ◽  
Cleavage Furrow ◽  
Molecule Inhibitor ◽  
Colorectal Cancer Cells ◽  
Spindle Midzone

The mitotic protein polo-like kinase 4 (PLK4) plays a critical role in centrosome duplication for cell division. By using immunofluorescence, we confirm that PLK4 is localized to centrosomes. In addition, we find that phospho-PLK4 (pPLK4) is cleaved and distributed to kinetochores (metaphase and anaphase), spindle midzone/cleavage furrow (anaphase and telophase), and midbody (cytokinesis) during cell division in immortalized epithelial cells as well as breast, ovarian, and colorectal cancer cells. The distribution of pPLK4 midzone/cleavage furrow and midbody positions pPLK4 to play a functional role in cytokinesis. Indeed, we found that inhibition of PLK4 kinase activity with a small-molecule inhibitor, CFI-400945, prevents translocation to the spindle midzone/cleavage furrow and prevents cellular abscission, leading to the generation of cells with polyploidy, increased numbers of duplicated centrosomes, and vulnerability to anaphase or mitotic catastrophe. The regulatory role of PLK4 in cytokinesis makes it a potential target for therapeutic intervention in appropriately selected cancers.

scholarly journals Recent Advances of the NLRP3 Inflammasome in Central Nervous System Disorders

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Keren Zhou ◽  
Ligen Shi ◽  
Yan Wang ◽  
Sheng Chen ◽  
Jianmin Zhang
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Nlrp3 Inflammasome ◽  
Hemorrhagic Stroke ◽  
Interleukin 1 ◽  
Critical Role ◽  
Interleukin 18 ◽  
Cns Diseases ◽  
Promising Therapeutic Target

Inflammasomes are multiprotein complexes that trigger the activation of caspases-1 and subsequently the maturation of proinflammatory cytokines interleukin-1βand interleukin-18. These cytokines play a critical role in mediating inflammation and innate immunity response. Among various inflammasome complexes, the NLRP3 inflammasome is the best characterized, which has been demonstrated as a crucial role in various diseases. Here, we review recently described mechanisms that are involved in the activation and regulation of NLRP3 inflammasome. In addition, we summarize the recent researches on the role of NLRP3 inflammasome in central nervous system (CNS) diseases, including traumatic brain injury, ischemic stroke and hemorrhagic stroke, brain tumor, neurodegenerative diseases, and other CNS diseases. In conclusion, the NLRP3 inflammasome may be a promising therapeutic target for these CNS diseases.

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