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Irak4

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https://www.readbyqxmd.com/read/29531937/corrigendum-irak4-deficiency-in-a-patient-with-recurrent-pneumococcal-infections-case-report-and-review-of-the-literature
#1
Karina S Gobin, Mary Hintermeyer, Bertrand Boisson, Maya Chrabieh, Pegah Ghandil, Anne Puel, Capucine Picard, Jean-Laurent Casanova, John Routes, James Verbsky
[This corrects the article on p. 83 in vol. 5, PMID: 28503543.].
2018: Frontiers in Pediatrics
https://www.readbyqxmd.com/read/29483095/irak1-augments-cancer-stemness-and-drug-resistance-via-the-ap-1-akr1b10-signaling-cascade-in-hepatocellular-carcinoma
#2
Bowie Y Cheng, Eunice Y Lau, Hoi-Wing Leung, Carmen Oi-Ning Leung, Nicole P Ho, Shilpa Gurung, Lily K Cheng, Chi Ho Lin, Regina Cheuk-Lam Lo, Stephanie Ma, Irene Oi-Lin Ng, Terence K Lee
Frequent relapse and drug resistance in patients with hepatocellular carcinoma (HCC) can be attributed to the existence of tumor-initiating cells (T-IC) within the tumor bulk. Therefore, targeting liver T-IC may improve the prognosis of these patients. From transcriptome sequencing of 16 pairs of clinical HCC samples, we report that interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway is significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patient survival...
February 26, 2018: Cancer Research
https://www.readbyqxmd.com/read/29482609/microrna-302b-negatively-regulates-il-1%C3%AE-production-in-response-to-msu-crystals-by-targeting-irak4-and-epha2
#3
Teng Ma, Xiao Liu, Zhifu Cen, Chuan Xin, Mingfeng Guo, Chaoyu Zou, Wenpeng Song, Rou Xie, Kailun Wang, Hong Zhou, Jun Zhang, Zhen Wang, Ce Bian, Kaijun Cui, Jiong Li, Yu-Quan Wei, Jing Li, Xikun Zhou
BACKGROUND: Interleukin-1β (IL-1β) is a pivotal proinflammatory cytokine that is strongly associated with the inflammation of gout. However, the underlying mechanism through which the production of IL-1β is regulated has not been fully elucidated. Our previous work identified that miR-302b had an important immune regulatory role in bacterial lung infections. This study was conducted to evaluate the function of miR-302b on monosodium urate (MSU) crystal-induced inflammation and its mechanism...
February 26, 2018: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/29468521/identification-of-a-constitutively-active-mutant-mouse-irak2-by-retroviral-expression-screening
#4
Yanmei Liu, Weilan Yin, Lingqing Xu, Helin Zhang, Qian Liu, Weiguo Yin
To identify the importance of IRAK2 kinase activity in TLR-mediated signaling pathways, we constructed a retroviral vector harboring either a mouse IRAK2 gene (IRAK2-WT) or with its mutant with loss of function of its ATP-binding site (IRAK2-KD). Further, we comparatively analyzed for the gain of function and modulations in TLR-mediated signaling pathways in IRAK2 knockout (IRAK2-KO) macrophages upon introduction of the IRAK2-WT retroviral constructs. The pBS/IRAK2-KD with the ATP-binding site mutation in IRAK2 was obtained by using site-specific mutagenesis...
February 21, 2018: Molecular Biotechnology
https://www.readbyqxmd.com/read/29400698/clonally-expanded-%C3%AE-%C3%AE-t-cells-protect-against-staphylococcus-aureus-skin-reinfection
#5
Carly A Dillen, Bret L Pinsker, Alina I Marusina, Alexander A Merleev, Orly N Farber, Haiyun Liu, Nathan K Archer, Da B Lee, Yu Wang, Roger V Ortines, Steven K Lee, Mark C Marchitto, Shuting S Cai, Alyssa G Ashbaugh, Larissa S May, Steven M Holland, Alexandra F Freeman, Loren G Miller, Michael R Yeaman, Scott I Simon, Joshua D Milner, Emanual Maverakis, Lloyd S Miller
The mechanisms that mediate durable protection against Staphylococcus aureus skin reinfections are unclear, as recurrences are common despite high antibody titers and memory T cells. Here, we developed a mouse model of S. aureus skin reinfection to investigate protective memory responses. In contrast with WT mice, IL-1β-deficient mice exhibited poor neutrophil recruitment and bacterial clearance during primary infection that was rescued during secondary S. aureus challenge. The γδ T cells from skin-draining LNs utilized compensatory T cell-intrinsic TLR2/MyD88 signaling to mediate rescue by trafficking and producing TNF and IFN-γ, which restored neutrophil recruitment and promoted bacterial clearance...
March 1, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29398441/optimization-of-permeability-in-a-series-of-pyrrolotriazine-inhibitors-of-irak4
#6
Sébastien L Degorce, Rana Anjum, Keith S Dillman, Lisa Drew, Sam D Groombridge, Christopher T Halsall, Eva M Lenz, Nicola A Lindsay, Michele F Mayo, Jennifer H Pink, Graeme R Robb, James S Scott, Stephen Stokes, Yafeng Xue
We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor...
January 17, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29363544/tumor-stroma-il1%C3%AE-irak4-feedforward-circuitry-drives-tumor-fibrosis-chemoresistance-and-poor-prognosis-in-pancreatic-cancer
#7
Daoxiang Zhang, Lin Li, Hongmei Jiang, Qiong Li, Andrea Wang-Gillam, Jinsheng Yu, Richard Head, Jingxia Liu, Marianna B Ruzinova, Kian-Huat Lim
Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but success in the clinic has thus far been limited. Preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAF) carries a risk of accelerating PDAC progression, underscoring the need to concurrently target key signaling mechanisms that drive the malignant attributes of both CAF and PDAC cells. We previously reported that inhibition of IL1 receptor-associated kinase 4 (IRAK4) suppresses NFκB activity and promotes response to chemotherapy in PDAC cells...
April 1, 2018: Cancer Research
https://www.readbyqxmd.com/read/29341132/acanthoic-acid-suppresses-lipin1-2-via-tlr4-and-irak4-signalling-pathways-in-etoh-and-lipopolysaccharide-induced-hepatic-lipogenesis
#8
Jian Song, Xin Han, You-Li Yao, Ya-Mei Li, Jing Zhang, Dan-Yang Shao, Li-Shuang Hou, Ying Fan, Shun-Zong Song, Li-Hua Lian, Ji-Xing Nan, Yan-Ling Wu
OBJECTIVES: In alcoholic liver disease, alcohol and lipopolysaccharide (LPS) are major stimulation factors of hepatic lipogenesis. Our objective was to determine the protective mechanism of acanthoic acid (AA) in EtOH- and LPS-induced hepatic lipogenesis. METHODS: HSC-T6 cells were treated with ethanol (200 mm) plus LPS (1 μg/ml) for 1 h, followed by AA (10 or 20 μm) for another 6 h. C57BL/6 mice were pretreated with of AA (20 and 40 mg/kg) or equal volume of saline and then exposed to three doses of ethanol (5 g/kg body weight) within 24 h...
January 17, 2018: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/29242191/the-inducible-microrna-203-in-fish-represses-the-inflammatory-responses-to-gram-negative-bacteria-by-targeting-il-1-receptor-associated-kinase-4
#9
Tianjun Xu, Qing Chu, Junxia Cui, Xueyan Zhao
Innate immune responses are the first defense against pathogenic invaders. Activation and termination of these immune responses are regulated by several mechanisms. MicroRNAs (miRNAs), a group of small non-coding RNAs, have been implicated in the regulation of a spectrum of both physiological and pathological conditions, including immune responses. Although the immune regulatory miRNA networks in higher vertebrates have been well described, regulation of these responses in fish species is poorly understood...
January 26, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29208712/crystal-structure-of-human-irak1
#10
Li Wang, Qi Qiao, Ryan Ferrao, Chen Shen, John M Hatcher, Sara J Buhrlage, Nathanael S Gray, Hao Wu
Interleukin 1 (IL-1) receptor-associated kinases (IRAKs) are serine/threonine kinases that play critical roles in initiating innate immune responses against foreign pathogens and other types of dangers through their role in Toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) mediated signaling pathways. Upon ligand binding, TLRs and IL-1Rs recruit adaptor proteins, such as myeloid differentiation primary response gene 88 (MyD88), to the membrane, which in turn recruit IRAKs via the death domains in these proteins to form the Myddosome complex, leading to IRAK kinase activation...
December 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29177859/examining-myddosome-formation-by-luminescence-based-mammalian-interactome-mapping-lumier
#11
Olaf-Oliver Wolz, Manfred Koegl, Alexander N R Weber
Recent structural, biochemical, and functional studies have led to the notion that many of the post-receptor signaling complexes in innate immunity have a multimeric, multi-protein architecture whose hierarchical assembly is vital for function. The Myddosome is a post-receptor complex in the cytoplasmic signaling of Toll-like receptors (TLR) and the Interleukin-1 receptor (IL-1R), involving the proteins MyD88, IL-1R-associated kinase 4 (IRAK4), and IRAK2. Its importance is strikingly illustrated by the fact that rare germline mutations in MYD88 causing high susceptibility to infections are characterized by failure to assemble Myddosomes; conversely, gain-of-function MYD88 mutations leading to oncogenic hyperactivation of NF-κB show increased Myddosome formation...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29172502/discovery-and-optimization-of-pyrrolopyrimidine-inhibitors-of-interleukin-1-receptor-associated-kinase-4-irak4-for-the-treatment-of-mutant-myd88-l265p-diffuse-large-b-cell-lymphoma
#12
James S Scott, Sébastien L Degorce, Rana Anjum, Janet Culshaw, Robert D M Davies, Nichola L Davies, Keith S Dillman, James E Dowling, Lisa Drew, Andrew D Ferguson, Sam D Groombridge, Christopher T Halsall, Julian A Hudson, Scott Lamont, Nicola A Lindsay, Stacey K Marden, Michele F Mayo, J Elizabeth Pease, David R Perkins, Jennifer H Pink, Graeme R Robb, Alan Rosen, Minhui Shen, Claire McWhirter, Dedong Wu
Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations...
December 28, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29142761/-aeromonas-hydrophila-utilizes-tlr4-topology-for-synchronous-activation-of-myd88-and-trif-to-orchestrate-anti-inflammatory-responses-in-zebrafish
#13
Nidhi Srivastava, Asha Shelly, Manmohan Kumar, Archana Pant, Bhabatosh Das, Tanmay Majumdar, Shibnath Mazumder
Toll-like receptor 4 (TLR4) plays a critical role in host immunity against Gram-negative bacteria. It transduces signals through two distinct TIR-domain-containing adaptors, MyD88 and TRIF, which function at the plasma membrane and endosomes, respectively. Using zebrafish Aeromonas hydrophila infection model, we demonstrate that synchronization of MyD88 and TRIF dependent pathways is critical for determining the fate of infection. Zebrafish were infected with A. hydrophila, and bacterial recovery studies suggested its effective persistence inside the host...
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/29127936/synthesis-of-n-3-4-11-c-methylpiperazin-1-yl-1-5-methylpyridin-2-yl-1h-pyrazol-5-yl-pyrazolo-1-5-a-pyrimidine-3-carboxamide-as-a-new-potential-pet-agent-for-imaging-of-irak4-enzyme-in-neuroinflammation
#14
Xiaohong Wang, Wenzhi Xu, Caihong Miao, Fugui Dong, Wei Li, Min Wang, Mingzhang Gao, Qi-Huang Zheng, Zhidong Xu
The reference standard N-(3-(4-methylpiperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (9) and its demethylated precursor N-(1-(5-methylpyridin-2-yl)-3-(piperazin-1-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide (8) were synthesized from pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and ethyl 2-cyanoacetate with overall chemical yield 13% in nine steps and 14% in eight steps, respectively. The target tracer N-(3-(4-[11 C]methylpiperazin-1-yl)-1-(5-methylpyridin-2-yl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ([11 C]9) was prepared from its precursor with [11 C]CH3 OTf through N-[11 C]methylation and isolated by HPLC combined with SPE in 50-60% radiochemical yield, based on [11 C]CO2 and decay corrected to EOB...
February 2018: Applied Radiation and Isotopes
https://www.readbyqxmd.com/read/29108825/targeting-interferons-and-their-pathways-in-systemic-lupus-erythematosus
#15
REVIEW
François Chasset, Laurent Arnaud
Significant advances in the understanding of the molecular basis of innate immunity have led to the identification of interferons (IFNs), particularly IFN-α, as central mediators in the pathogenesis of Systemic Lupus Erythematosus. Therefore, targeting of IFNs and of their downstream pathways has emerged as important developments for novel drug research in SLE. Based on this, several specific interferon blocking strategies using anti-IFN-α antibodies, anti-type I interferon receptor antibodies, Interferon-α-kinoid, or anti-IFN-γ antibodies have all been assessed in recent clinical trials...
January 2018: Autoimmunity Reviews
https://www.readbyqxmd.com/read/29093371/-identification-of-biomarkers-for-tubular-injury-and-interstitial-fibrosis-in-chronic-kidney-disease
#16
REVIEW
Shunsaku Nakagawa
 In chronic kidney disease (CKD), progressive nephron loss causes tubulointerstitial fibrosis and progressive tubular injury. Recent identification of the major cell populations of myofibroblast precursors in the kidney has enabled us to dissect the fibrogenic process after tubular injury. Kidney pericytes are a possible precursor of myofibroblasts, and may be promising targets for treating fibrogenesis. Our recent studies have shown that pericytes activate Toll-like receptor (TLR) 2/4- and myeloid differentiation primary response 88 (MyD88)-dependent proinflammatory signaling in response to renal tubular injury...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/29080686/cloning-expression-pattern-and-functional-characterization-of-interleukin-1-receptor-associated-kinase-4-an-important-mediator-of-the-toll-like-receptor-signaling-pathway-from-artemia-sinica
#17
Di Wang, Yu Xia, Zao Zhang, Zhangping Wang, Daochuan Zhang, Hong Yin
As a crucial component of Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) signaling pathways, IL-1R--associated kinase 4 (IRAK-4) plays a central role in innate immunity and embryonic development. Herein, we have characterized the full length cDNA of IRAK4 from Artemia sinica. Molecular characterization revealed that the sequence includes a 2550 bp open reading frame, encoding a predicted protein of 849 amino acids. The predicted protein contains a death domain in the N-terminus and two serine/threonine/tyrosine protein kinasedomains...
January 2018: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28988892/the-il-1%C3%AE-signalling-pathway-and-its-role-in-regulating-pro-inflammatory-and-pro-labour-mediators-in-human-primary-myometrial-cells
#18
Martha Lappas
Interleukin (IL)-1β plays a central role in the processes of human labour and delivery. The adaptor proteins involved in the IL-1β signalling pathway in human myometrium are not known. This study sought to determine the role of the adaptor proteins myeloid differentiation primary response 88 (MyD88), tumour necrosis factor receptor-associated factor 6 (TRAF6), IL-1 receptor-associated kinase 4 (IRAK4) and transforming growth factor beta-activated kinase 1 (TAK1) in IL-1β-induced formation of pro-inflammatory and pro-labour mediators in human myometrium...
December 2017: Reproductive Biology
https://www.readbyqxmd.com/read/28964808/acanthoic-acid-protectsagainst-ethanol-induced-liver-injury-possible-role-of-ampk-activation-and-irak4-inhibition
#19
You-Li Yao, Xin Han, Jian Song, Jing Zhang, Ya-Mei Li, Li-Hua Lian, Yan-Ling Wu, Ji-Xing Nan
The aim of this study was to investigate the effects of acanthoic acid (AA) on the regulation of inflammatory response, lipid accumulation, and fibrosis via AMPK- IRAK4 signaling against chronic alcohol consumption in mice. Ethanol-induced liver injury was induced in male mice by Lieber-DeCarli diet for 28d. And mice in AA groups were gavaged with AA (20 or 40mg/kg) for 28d. AA treatment significantly decreased serum AST and TG, hepatic TG levels, serum ethanol and LPS levels compared with chronic ethanol administration...
November 5, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28958897/the-tlr13-myd88-nf-%C3%AE%C2%BAb-signalling-pathway-of-cyclina-sinensis-plays-vital-roles-in-innate-immune-responses
#20
Yipeng Ren, Dan Ding, Baoping Pan, Wenjun Bu
Toll-like receptors, the best known pattern recognition receptors, play important roles in recognizing non-self molecules and binding pathogen-associated molecular patterns in the innate immune system. In the present research, the cDNA and protein characterization of the TLR signalling pathway genes including IRAK4, TRAK6 and IKKα (named CsIRAK4, CsTRAF6 and CsIKKα, respectively) with the typical motifs from Cyclina sinensis showed significant similarity with their homologues from other shellfish. Furthermore, the mRNA transcripts of these three genes are ubiquitously expressed in all tissues tested and are dominantly expressed in C...
September 25, 2017: Fish & Shellfish Immunology
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