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https://www.readbyqxmd.com/read/28099848/biophysical-attributes-of-cpg-presentation-control-tlr9-signaling-to-differentially-polarize-systemic-immune-responses
#1
Jardin A Leleux, Pallab Pradhan, Krishnendu Roy
It is currently unknown whether and how mammalian pathogen recognition receptors (PRRs) respond to biophysical patterns of pathogen-associated molecular danger signals. Using synthetic pathogen-like particles (PLPs) that mimic physical properties of bacteria or large viruses, we have discovered that the quality and quantity of Toll-like receptor 9 (TLR9) signaling by CpG in mouse dendritic cells (mDCs) are uniquely dependent on biophysical attributes; specifically, the surface density of CpG and size of the presenting PLP...
January 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/28092460/a-three-dimensional-lymphatic-endothelial-cell-tube-formation-assay-to-identify-novel-kinases-involved-in-lymphatic-vessel-remodeling
#2
T Jessica Gambino, Steven P Williams, Carol Caesar, Daniel Resnick, Cameron J Nowell, Rae H Farnsworth, Marc G Achen, Steven A Stacker, Tara Karnezis
The lymphatic system is a series of vessels that transport cells and excess fluid from tissues to the blood vascular system. Normally quiescent, the lymphatics can grow or remodel in response to developmental, immunological, or cells pathological stimuli. Lymphatic vessels comprise lymphatic endothelial cells (LECs) that can respond to external growth factors by undergoing proliferation, migration, adhesion, and tube and lumen formation into new vessel structures, a process known as lymphangiogenesis. To understand the key gene and signaling pathways necessary for lymphangiogenesis and lymphatic vessel remodeling, we have developed a three-dimensional LEC tube formation assay to explore the role of kinase signaling in these processes...
January 2017: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/28088611/lactobacillus-paracasei-modulates-lps-induced-inflammatory-cytokine-release-by-monocyte-macrophages-via-the-up-regulation-of-negative-regulators-of-nf-kappab-signaling-in-a-tlr2-dependent-manner
#3
Ke-Yi Sun, Dong-Hua Xu, Chao Xie, Susan Plummer, James Tang, Xiao Fan Yang, Xiao Hui Ji
The application of the probiotic lactobacillus is suggested in the treatment of some inflammatory diseases of intestines due to its potential ability to attenuate inflammation. However, the mechanism is not completely understood. In PBMCs, Lactobacillus paracasei (L. Paracasei) down-regulated the LPS-induced production of TNF-α and IL-6. Using a macrophage-like differentiated THP-1 cell line induced by PMA, we investigated the effect of L. paracasei on the production of pro-inflammatory cytokines by monocyte-macrophages...
January 12, 2017: Cytokine
https://www.readbyqxmd.com/read/28003376/selective-irak4-inhibition-attenuates-disease-in-murine-lupus-models-and-demonstrates-steroid-sparing-activity
#4
Shailesh Dudhgaonkar, Sourabh Ranade, Jignesh Nagar, Siva Subramani, Durga Shiv Prasad, Preethi Karunanithi, Ratika Srivastava, Kamala Venkatesh, Sabariya Selvam, Prasad Krishnamurthy, T Thanga Mariappan, Ajay Saxena, Li Fan, Dawn K Stetsko, Deborah A Holloway, Xin Li, Jun Zhu, Wen-Pin Yang, Stefan Ruepp, Satheesh Nair, Joseph Santella, John Duncia, John Hynes, Kim W McIntyre, Julie A Carman
The serine/threonine kinase IL-1R-associated kinase (IRAK)4 is a critical regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway...
February 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27989863/cloning-and-functional-characterization-of-irak4-in-large-yellow-croaker-larimichthys-crocea-that-associates-with-myd88-but-impairs-nf-%C3%AE%C2%BAb-activation
#5
Peng Fei Zou, Xue Na Huang, Cui Luan Yao, Qing Xue Sun, Ying Li, Qian Zhu, Zhen Xing Yu, Zhe Jun Fan
As crucial signaling transducer in Toll-like receptor (TLR) and interleukin (IL)-1 receptor (IL-1R) signaling pathway, IL-1R-associated kinase 4 (IRAK4) mediates downstream signaling cascades and plays important roles in innate and adaptive immune responses. In the present study, an IRAK4 orthologue was characterized from large yellow croaker (Larimichthys crocea), named Lc-IRAK4, with a conservative N-terminal death domain and a C-terminal protein kinase domain. The genome of Lc-IRAK4 is structured into eleven exons and ten introns...
December 15, 2016: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/27916973/fibrosis-pericyte-myd88-and-irak4-signalling-in-fibrosis
#6
Susan J Allison
No abstract text is available yet for this article.
February 2017: Nature Reviews. Nephrology
https://www.readbyqxmd.com/read/27895398/dysregulation-of-innate-immunity-in-ulcerative-colitis-patients-who-fail-anti-tumor-necrosis-factor-therapy
#7
Angela C Baird, Dominic Mallon, Graham Radford-Smith, Julien Boyer, Thierry Piche, Susan L Prescott, Ian C Lawrance, Meri K Tulic
AIM: To study the innate immune function in ulcerative colitis (UC) patients who fail to respond to anti-tumor necrosis factor (TNF) therapy. METHODS: Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell (PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor (TLR) expression and cytokine production post TLR stimulation was assessed in UC "responders" (n = 12) and "non-responders" (n = 12) and compared to healthy controls (n = 12)...
November 7, 2016: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/27890916/polydatin-ameliorates-staphylococcus-aureus-induced-mastitis-in-mice-via-inhibiting-tlr2-mediated-activation-of-the-p38-mapk-nf-%C3%AE%C2%BAb-pathway
#8
Kang-Feng Jiang, Gan Zhao, Gan-Zhen Deng, Hai-Chong Wu, Nan-Nan Yin, Xiu-Ying Chen, Chang-Wei Qiu, Xiu-Li Peng
Recent studies show that Polydatin (PD) extracted from the roots of Polygonum cuspidatum Sieb, a widely used traditional Chinese remedies, possesses anti-inflammatory activity in several experimental models. In this study, we investigated the anti-inflammatory effects of PD on Staphylococcus aureus-induced mastitis in mice and elucidated the potential mechanisms. In mice with S aureus-induced mastitis, administration of PD (15, 30, 45 mg/kg, ip) or dexamethasone (Dex, 5 mg/kg, ip) significantly suppressed the infiltration of inflammatory cells, ameliorated the mammary structural damage, and inhibited the activity of myeloperoxidase, a biomarker of neutrophils accumulation...
November 28, 2016: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/27881653/microrna-373-facilitates-the-replication-of-porcine-reproductive-and-respiratory-syndrome-virus-by-its-negative-regulation-of-type-i-interferon-induction
#9
Jing Chen, Xibao Shi, Xiaozhuan Zhang, Aiping Wang, Li Wang, Yanyan Yang, Ruiguang Deng, Gai-Ping Zhang
: MicroRNAs (miRNAs) play an important role in the regulation of immune responses. Previous studies have indicated that dysregulating the miRNAs leads to the immunosuppression of porcine reproductive and respiratory syndrome virus (PRRSV). However, it is not clear how PRRSV regulates the expression of host miRNA, which may lead to immune escape or promote the replication of the virus. The present work suggests that PRRSV upregulated the expression of miR-373 through elevating the expression of specificity protein 1 (Sp1) in MARC-145 cells...
February 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/27869651/pericyte-myd88-and-irak4-control-inflammatory-and-fibrotic-responses-to-tissue-injury
#10
Irina A Leaf, Shunsaku Nakagawa, Bryce G Johnson, Jin Joo Cha, Kristen Mittelsteadt, Kevin M Guckian, Ivan G Gomez, William A Altemeier, Jeremy S Duffield
Fibrotic disease is associated with matrix deposition that results in the loss of organ function. Pericytes, the precursors of myofibroblasts, are a source of pathological matrix collagens and may be promising targets for treating fibrogenesis. Here, we have shown that pericytes activate a TLR2/4- and MyD88-dependent proinflammatory program in response to tissue injury. Similarly to classic immune cells, pericytes activate the NLRP3 inflammasome, leading to IL-1β and IL-18 secretion. Released IL-1β signals through pericyte MyD88 to amplify this response...
January 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27864528/irak1-and-irak4-promote-phosphorylation-ubiquitination-and-degradation-of-myd88-adaptor-like-mal
#11
Aisling Dunne, Susan Carpenter, Constantinos Brikos, Pearl Gray, Astrid Strelow, Holger Wesche, Nick Morrice, Luke A J O'Neill
No abstract text is available yet for this article.
November 18, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27845762/recent-progress-in-the-molecular-recognition-and-therapeutic-importance-of-interleukin-1-receptor-associated-kinase-4
#12
REVIEW
Mahesh Chandra Patra, Sangdun Choi
Toll-like receptors (TLRs) are the most upstream pattern recognition receptors in the cell, which detect pathogen associated molecular patterns and initiate signal transduction, culminating in the transcription of pro-inflammatory cytokines and antiviral interferon. Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key mediator in TLR (except for TLR3) and interleukin-1 receptor signaling pathways. The loss of kinase function of IRAK4 is associated with increased susceptibility to various pathogens, while its over-activation causes autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and cancer...
November 13, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27807192/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
#13
Sambit K Nanda, Marta Lopez-Pelaez, J Simon C Arthur, Francesco Marchesi, Philip Cohen
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...
December 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27702822/constitutive-irak4-activation-underlies-poor-prognosis-and-chemoresistance-in-pancreatic-ductal-adenocarcinoma
#14
Daoxiang Zhang, Lin Li, Hongmei Jiang, Brett L Knolhoff, Albert C Lockhart, Andrea Wang-Gillam, David G DeNardo, Marianna B Ruzinova, Kian-Huat Lim
PURPOSE: Aberrant activation of the NF-κB transcription factors underlies the aggressive behavior and poor outcome of pancreatic ductal adenocarcinoma (PDAC). However, clinically effective and safe NF-κB inhibitors are not yet available. Because NF-κB transcription factors can be activated by the interleukin-1 receptor-associated kinases (IRAKs) downstream of the Toll-like receptors (TLRs), but has not been explored in PDAC, we sought to investigate the role of IRAKs in the pathobiology of PDAC...
October 4, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27676214/tlr4-acts-as-a-death-receptor-for-ultraviolet-radiation-uvr-through-irak-independent-and-fadd-dependent-pathway-in-macrophages
#15
Hua Zhou, Erin Harberts, Rita Fishelevich, Anthony A Gaspari
UVR-induced apoptosis in cutaneous antigen presenting cells (APC) causes systemic immune suppression and is dependent on TLR4/MyD88 signaling, but the apoptotic signaling pathways have not been defined. Macrophages pre-treated with lipopolysaccharide (LPS) were unresponsive to subsequent LPS treatment; however, but were susceptible to UVR-induced apoptosis. Macrophage survival and apoptotic events after UVR were also unaffected by treatment with TLR4 antagonists, a blocking IgG or a TLR4 analog antagonist, suggesting that UVR cell death is independent of a soluble ligand...
September 27, 2016: Experimental Dermatology
https://www.readbyqxmd.com/read/27624059/paeonol-suppresses-neuroinflammatory-responses-in-lps-activated-microglia-cells
#16
Li Xia He, Xiaoyun Tong, Jing Zeng, Yuanqing Tu, Saicun Wu, Manping Li, Huaming Deng, Miaomiao Zhu, Xiucun Li, Hong Nie, Li Yang, Feng Huang
In this work, we assessed the anti-inflammatory effects of paeonol (PAE) in LPS-activated N9 microglia cells, as well as its underlying molecular mechanisms. PAE had no adverse effect on the viability of murine microglia N9 cell line within a broad range (0.12∼75 μM). When N9 cell line was activated by LPS, PAE (0.6, 3, 15 μM) significantly suppressed the release of proinflammatory products, such as nitric oxide (NO), interleukin-1β (IL-1β), and prostaglandin E2 (PGE2), demonstrated by the ELISA assay...
December 2016: Inflammation
https://www.readbyqxmd.com/read/27579619/i%C3%AE%C2%BAb%C3%AE-an-emerging-player-in-cancer
#17
REVIEW
Marie Willems, Nadège Dubois, Lucia Musumeci, Vincent Bours, Pierre A Robe
IκBζ, an atypical member of the nuclear IκB family of proteins, is expressed at low levels in most resting cells, but is induced upon stimulation of Toll-like/IL-1 receptors through an IRAK1/IRAK4/NFκB-dependent pathway. Like its homolog Bcl3, IκBζ can regulate the transcription of a set of inflamatory genes through its association with the p50 or p52 subunits of NF-κB. Long studied as a key component of the immune response, IκBζ emerges as an important regulator of inflammation, cell proliferation and survival...
4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27476420/efforts-towards-the-optimization-of-a-bi-aryl-class-of-potent-irak4-inhibitors
#18
Jennifer Hanisak, W Michael Seganish, William T McElroy, Haiquin Tang, Rui Zhang, Hon-Chung Tsui, Theirry Fischmann, Deen Tulshian, James Tata, Christopher Sondey, Kristine Devito, James Fossetta, Charles G Garlisi, Daniel Lundell, Xiaoda Niu
IRAK4 has been identified as potential therapeutic target for inflammatory and autoimmune diseases. Herein we report the identification and initial SAR studies of a new class of pyrazole containing IRAK4 inhibitors designed to expand chemical diversity and improve off target activity of a previously identified series. These compounds maintain potent IRAK4 activity and desirable ligand efficiency. Rat clearance and a variety of off target activities were also examined, resulting in encouraging data with tractable SAR...
September 1, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27432718/variation-of-46-innate-immune-genes-evaluated-for-their-contribution-in-pneumococcal-meningitis-susceptibility-and-outcome
#19
Bart Ferwerda, Mercedes Valls Serón, Aldo Jongejan, Aeilko H Zwinderman, Madelijn Geldhoff, Arie van der Ende, Frank Baas, Matthijs C Brouwer, Diederik van de Beek
Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Early recognition of the pathogen and subsequent innate immune response play a vital role in disease susceptibility and outcome. Genetic variations in innate immune genes can alter the immune response and influence susceptibility and outcome of meningitis disease. Here we conducted a sequencing study of coding regions from 46 innate immune genes in 435 pneumococcal meningitis patients and 416 controls, to determine the role of genetic variation on pneumococcal meningitis susceptibility and disease outcome...
August 2016: EBioMedicine
https://www.readbyqxmd.com/read/27310003/inhibitors-of-interleukin-1-receptor-associated-kinase-4-irak4-a-patent-review-2012-2015
#20
W Michael Seganish
INTRODUCTION: IRAK4 is located proximal to TLR/IL-1 receptors, and in preclinical studies, inhibits downstream signaling from these receptors. The development of novel small molecule inhibitors of this kinase has the potential to lead to new therapeutics to treat diseases such as rheumatoid arthritis, lupus, and lymphomas. AREAS COVERED: The aim of this review is to summarize the recent patent literature (2012-2015) surrounding small molecule inhibitors of IRAK4...
August 2016: Expert Opinion on Therapeutic Patents
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