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https://www.readbyqxmd.com/read/28432060/toll-like-receptor-2-tlr2-dominance-over-tlr4-in-stressful-conditions-for-its-detrimental-role-in-the-heart
#1
Ashim K Bagchi, Gauri Akolkar, Soma Mandal, Prathapan Ayyappan, Xi Yang, Pawan K Singal
It has been suggested that toll-like receptor 4 (TLR4) promotes interleukin-10 (IL-10)-mediated cardiac cell survival while another receptor, TLR2, from the same family is detrimental. Here we examined the interactive role of these two innate signaling molecules under stressful conditions including interleukin-10 knockout (IL-10(-/-)) mice, global ischemia/reperfusion (I/R) injury in rat hearts and in-vitro shRNA experimental models in presence or absence of IL-10 (10ng/ml). Circulating and myocardial levels of tumor necrosis factor-α (TNF-α) as well as apoptosis and fibrosis were higher in IL-10(-/-) mice...
April 21, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28295231/deficiency-in-irak4-activity-attenuates-manifestations-of-murine-lupus
#2
Michael Murphy, Goutham Pattabiraman, Tissa T Manavalan, Andrei E Medvedev
Interleukin-1 receptor-associated kinase (IRAK) 4 mediates host defense against infections. As an active kinase, IRAK4 elicits full spectra of myeloid differentiation primary response protein (MyD) 88-dependent responses, while kinase-inactive IRAK4 induces a subset of cytokines and negative regulators whose expression is not regulated by mRNA stability. IRAK4 kinase activity is critical for resistance against Streptococcus pneumoniae, but its involvement in autoimmunity is incompletely understood. In this study, we determined the role of IRAK4 kinase activity in murine lupus...
May 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28213090/glycyrrhetinic-acid-attenuates-lipopolysaccharide-induced-fulminant-hepatic-failure-in-d-galactosamine-sensitized-mice-by-up-regulating-expression-of-interleukin-1-receptor-associated-kinase-m
#3
Xinru Yin, Xia Gong, Li Zhang, Rong Jiang, Ge Kuang, Bin Wang, Xinyu Chen, Jingyuan Wan
Glycyrrhetinic acid (GA), the main active ingredient of licorice, reportedly has anti-inflammatory and hepatoprotective properties, but its molecular mechanisms remain be elusive. In the present study, Balb/c mice were pretreated with GA (10, 30, or 100mg/kg) 1h before lipopolysaccharide (LPS)/d-galactosamine (D-GalN) administration. In other in vitro experiment, RAW264.7 macrophages were pretreated with GA before LPS exposure. The mortality, hepatic tissue histology, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed...
February 14, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28120642/a-novel-mouse-model-of-conditional-irak-m-deficiency-in-myeloid-cells-application-in-lung-pseudomonas-aeruginosa-infection
#4
Di Jiang, Jennifer Matsuda, Reena Berman, Niccolette Schaefer, Connor Stevenson, James Gross, Bicheng Zhang, Amelia Sanchez, Liwu Li, Hong Wei Chu
Myeloid cells such as macrophages are critical to innate defense against infection. IL-1 receptor-associated kinase M (IRAK-M) is a negative regulator of TLR signaling during bacterial infection, but the role of myeloid cell IRAK-M in bacterial infection is unclear. Our goal was to generate a novel conditional knockout mouse model to define the role of myeloid cell IRAK-M during bacterial infection. Myeloid cell-specific IRAK-M knockout mice were generated by crossing IRAK-M floxed mice with LysM-Cre knock-in mice...
February 2017: Innate Immunity
https://www.readbyqxmd.com/read/28118607/middle-east-respiratory-syndrome-corona-virus-spike-glycoprotein-suppresses-macrophage-responses-via-dpp4-mediated-induction-of-irak-m-and-ppar%C3%AE
#5
Ahmed A Al-Qahtani, Konstantina Lyroni, Marina Aznaourova, Melpomeni Tseliou, Mashael R Al-Anazi, Mohammed N Al-Ahdal, Saad Alkahtani, George Sourvinos, Christos Tsatsanis
Middle East Respiratory Syndrome Corona Virus (MERS-CoV) is transmitted via the respiratory tract and causes severe Acute Respiratory Distress Syndrome by infecting lung epithelial cells and macrophages. Macrophages can readily recognize the virus and eliminate it. MERS-CoV infects cells via its Spike (S) glycoprotein that binds on Dipeptidyl-Peptidase 4 (DPP4) receptor present on macrophages. Whether this Spike/DPP4 association affects macrophage responses remains unknown. Herein we demonstrated that infection of macrophages with lentiviral particles pseudotyped with MERS-CoV S glycoprotein results in suppression of macrophage responses since it reduced the capacity of macrophages to produce TNFα and IL-6 in naive and LPS-activated THP-1 macrophages and augmented LPS-induced production of the immunosuppressive cytokine IL-10...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28090786/inorganic-nitrite-modulates-mirna-signatures-in-acute-myocardial-in-vivo-ischemia-reperfusion
#6
Ulrike B Hendgen-Cotta, Daniel Messiha, Sonja Esfeld, René Deenen, Tienush Rassaf, Matthias Totzeck
Acute myocardial infarction is the leading cause of mortality in the industrialized world. While it is essential to attempt an early reperfusion of ischemic myocardial territories, reperfusion itself adds damage to the heart, the ischemia-reperfusion (I/R) injury. Particularly the injury resulting from the very first minutes of reperfusion remains incompletely understood. MicroRNAs (miRNAs) are dynamic regulators in I/R injury. Nitric oxide (•NO) signaling, in turn, interacts with miRNA signaling. Our previous investigations showed that •NO signaling in I/R could be modulated by nitrite...
January 2017: Free Radical Research
https://www.readbyqxmd.com/read/28011933/epigenetic-and-transcriptional-regulation-of-irak-m-expression-in-macrophages
#7
Konstantina Lyroni, Andreas Patsalos, Maria G Daskalaki, Christina Doxaki, Birte Soennichsen, Mike Helms, Ioannis Liapis, Vassiliki Zacharioudaki, Sotirios C Kampranis, Christos Tsatsanis
During macrophage activation, expression of IL-1R-associated kinase (IRAK)-M is induced to suppress TLR-mediated responses and is a hallmark of endotoxin tolerance. Endotoxin tolerance requires tight regulation of genes occurring at the transcriptional and epigenetic levels. To identify novel regulators of IRAK-M, we used RAW 264.7 macrophages and performed a targeted RNA interference screen of genes encoding chromatin-modifying enzymes, signaling molecules, and transcription factors involved in macrophage activation...
December 23, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27939424/enhanced-mucosal-defense-and-reduced-tumor-burden-in-mice-with-the-compromised-negative-regulator-irak-m
#8
Daniel E Rothschild, Yao Zhang, Na Diao, Christina K Lee, Keqiang Chen, Clayton C Caswell, Daniel J Slade, Richard F Helm, Tanya LeRoith, Liwu Li, Irving C Allen
Aberrant inflammation is a hallmark of inflammatory bowel disease (IBD) and colorectal cancer. IRAK-M is a critical negative regulator of TLR signaling and overzealous inflammation. Here we utilize data from human studies and Irak-m(-/-) mice to elucidate the role of IRAK-M in the modulation of gastrointestinal immune system homeostasis. In human patients, IRAK-M expression is up-regulated during IBD and colorectal cancer. Further functional studies in mice revealed that Irak-m(-/-) animals are protected against colitis and colitis associated tumorigenesis...
February 2017: EBioMedicine
https://www.readbyqxmd.com/read/27832756/lactobacillus-acidophilus-alleviates-the-inflammatory-response-to-enterotoxigenic-escherichia-coli-k88-via-inhibition-of-the-nf-%C3%AE%C2%BAb-and-p38-mitogen-activated-protein-kinase-signaling-pathways-in-piglets
#9
Haihua Li, Lei Zhang, Longbin Chen, Qi Zhu, Wenjie Wang, Jiayun Qiao
BACKGROUND: A newly isolated L. acidophilus strain has been reported to have potential anti-inflammatory activities against lipopolysaccharide (LPS) challenge in piglet, while the details of the related inflammatory responses are limited. Here we aimed to analysis the ability of L. acidophilus to regulate inflammatory responses and to elucidate the mechanisms involved in its anti-inflammatory activity. RESULTS: The ETEC (enterotoxigenic Escherichia coli) K88-induced up-regulations of IL-1β, IL-8 and TNF-α were obviously inhibited by L...
November 10, 2016: BMC Microbiology
https://www.readbyqxmd.com/read/27824038/the-persistence-of-low-grade-inflammatory-monocytes-contributes-to-aggravated-atherosclerosis
#10
Shuo Geng, Keqiang Chen, Ruoxi Yuan, Liang Peng, Urmila Maitra, Na Diao, Chun Chen, Yao Zhang, Yuan Hu, Chen-Feng Qi, Susan Pierce, Wenhua Ling, Huabao Xiong, Liwu Li
Sustained low-grade inflammation mediated by non-resolving inflammatory monocytes has long been suspected in the pathogenesis of atherosclerosis; however, the molecular mechanisms responsible for the sustainment of non-resolving inflammatory monocytes during atherosclerosis are poorly understood. Here we observe that subclinical endotoxemia, often seen in humans with chronic inflammation, aggravates murine atherosclerosis through programming monocytes into a non-resolving inflammatory state with elevated Ly6C, CCR5, MCP-1 and reduced SR-B1...
November 8, 2016: Nature Communications
https://www.readbyqxmd.com/read/27562721/activator-protein-1-promotes-the-transcriptional-activation-of-irak-m
#11
Peipei Jin, Lulong Bo, Yongjian Liu, Wenbin Lu, Shengwei Lin, Jinjun Bian, Xiaoming Deng
Interleukin-1 receptor-associated kinase M (IRAK-M) is a well-known negative regulator for Toll-like receptor signaling, which can regulate immune homeostasis and tolerance in a number of pathological settings. However, the mechanism for IRAK-M regulation at transcriptional level remains largely unknown. In this study, a 1.4kb upstream sequence starting from the major IRAK-M transcriptional start site was cloned into luciferase reporter vector pGL3-basic to construct the full-length IRAK-M promoter. Luciferase reporter plasmids harboring the full-length and the deletion mutants of IRAK-M were transfected into 293T and A549 cells, and their relative luciferase activity was measured...
October 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27402699/dual-inhibition-of-rip2-and-irak1-4-regulates-il-1%C3%AE-and-il-6-in-sarcoidosis-alveolar-macrophages-and-peripheral-blood-mononuclear-cells
#12
Jaya Talreja, Harvinder Talwar, Nisar Ahmad, Ruchi Rastogi, Lobelia Samavati
Sarcoidosis is a multisystem granulomatous disease of unknown etiology that primarily affects the lungs. Our previous work indicates that activation of p38 plays a pivotal role in sarcoidosis inflammatory response. Therefore, we investigated the upstream kinase responsible for activation of p38 in sarcoidosis alveolar macrophages (AMs) and PBMCs. We identified that sustained p38 phosphorylation in sarcoidosis AMs and PBMCs is associated with active MAPK kinase 4 but not with MAPK kinase 3/6. Additionally, we found that sarcoidosis AMs exhibit a higher expression of IRAK1, IRAK-M, and receptor interacting protein 2 (Rip2)...
August 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27165738/multifaceted-role-of-irak-m-in-the-promotion-of-colon-carcinogenesis-via-barrier-dysfunction-and-stat3-oncoprotein-stabilization-in-tumors
#13
COMMENT
Brendan J Jenkins
Dysregulated interactions between the host immune system and gut microbiota can underpin inflammation, leading to colorectal cancer (CRC). In this issue of Cancer Cell, Kesselring et al. reveal a bimodal role of the TLR/IL-1R-signaling negative regulator, IRAK-M, in promoting tumoral microbial colonization and STAT3 oncoprotein stabilization during CRC.
May 9, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27150039/irak-m-expression-in-tumor-cells-supports-colorectal-cancer-progression-through-reduction-of-antimicrobial-defense-and-stabilization-of-stat3
#14
Rebecca Kesselring, Joachim Glaesner, Andreas Hiergeist, Elisabeth Naschberger, Helmut Neumann, Stefan M Brunner, Anja K Wege, Caroline Seebauer, Gudrun Köhl, Susanne Merkl, Roland S Croner, Christina Hackl, Michael Stürzl, Markus F Neurath, André Gessner, Hans-Juergen Schlitt, Edward K Geissler, Stefan Fichtner-Feigl
Colorectal cancer (CRC) is associated with loss of epithelial barrier integrity, which facilitates the interaction of the immunological microenvironment with the luminal microbiome, eliciting tumor-supportive inflammation. An important regulator of intestinal inflammatory responses is IRAK-M, a negative regulator of TLR signaling. Here we investigate the compartment-specific impact of IRAK-M on colorectal carcinogenesis using a mouse model. We demonstrate that IRAK-M is expressed in tumor cells due to combined TLR and Wnt activation...
May 9, 2016: Cancer Cell
https://www.readbyqxmd.com/read/26991073/preconditioning-with-recombinant-high-mobility-group-box-1-induces-ischemic-tolerance-in-a-rat-model-of-focal-cerebral-ischemia-reperfusion
#15
Chen Wang, Xiao-Xi Liu, Kai-Bin Huang, Su-Bing Yin, Jing-Jing Wei, Ya-Fang Hu, Yong Gu, Guo-Qing Zheng
Preconditioning with ligands of toll-like receptors (TLRs) is a powerful neuroprotective approach whereby a low dose of stimulus confers significant protection against subsequent substantial brain damage by reprogramming the ischemia-activated TLRs signaling. Herein, we aim to explore whether preconditioning with recombinant high-mobility group box 1 (rHMGB1), one of the TLRs ligands, decreases cerebral ischemia-reperfusion injury (IRI). Rats were intracerebroventricularly pretreated with rHMGB1, 1 or 3 days before induction of middle cerebral artery occlusion...
May 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/26669797/endothelial-cell-tolerance-to-lipopolysaccharide-challenge-is-induced-by-monophosphoryl-lipid-a
#16
Ryan J Stark, Hyehun Choi, Stephen R Koch, Benjamin A Fensterheim, Fred S Lamb, Edward R Sherwood
Prior exposure to lipopolysaccharide (LPS) produces a reduced or "tolerant" inflammatory response to subsequent challenges with LPS, however the potent pro-inflammatory effects of LPS limit its clinical benefit. The adjuvant monophosphoryl lipid A (MPLA) is a weak toll-like receptor 4 (TLR4) agonist that induces negligible inflammation but retains potent immunomodulatory properties. We postulated that pre-treatment with MPLA would inhibit the inflammatory response of endothelial cells to secondary LPS challenge...
March 2016: Clinical Science (1979-)
https://www.readbyqxmd.com/read/26542797/the-role-of-interleukin-receptor-associated-kinase-irak-m-in-regulation-of-myofibroblast-phenotype-in-vitro-and-in-an-experimental-model-of-non-reperfused-myocardial-infarction
#17
Amit Saxena, Arti V Shinde, Zaffar Haque, Yi-Jin Wu, Wei Chen, Ya Su, Nikolaos G Frangogiannis
In the infarcted myocardium, necrotic cardiomyocytes activate innate immune pathways, stimulating pro-inflammatory signaling cascades. Although inflammation plays an important role in clearance of the infarct from dead cells and matrix debris, repair of the infarcted heart requires timely activation of signals that negatively regulate the innate immune response, limiting inflammatory injury. We have previously demonstrated that Interleukin receptor-associated kinase (IRAK)-M, a member of the IRAK family that suppresses toll-like receptor/interleukin-1 signaling, is upregulated in the infarcted heart in both macrophages and fibroblasts, and restrains pro-inflammatory activation attenuating adverse remodeling...
December 2015: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/26462859/differential-expression-of-key-regulators-of-toll-like-receptors-in-ulcerative-colitis-and-crohn-s-disease-a-role-for-tollip-and-peroxisome-proliferator-activated-receptor-gamma
#18
P Fernandes, J MacSharry, T Darby, A Fanning, F Shanahan, A Houston, E Brint
The innate immune system is currently seen as the probable initiator of events which culminate in the development of inflammatory bowel disease (IBD) with Toll-like receptors (TLRs) known to be involved in this disease process. Many regulators of TLRs have been described, and dysregulation of these may also be important in the pathogenesis of IBD. The aim of this study was to perform a co-ordinated analysis of the expression levels of both key intestinal TLRs and their inhibitory proteins in the same IBD cohorts, both ulcerative colitis (UC) and Crohn's disease (CD), in order to evaluate the potential roles of these proteins in the pathogenesis of IBD...
March 2016: Clinical and Experimental Immunology
https://www.readbyqxmd.com/read/26454478/vibrio-cholerae-porin-ompu-induces-lps-tolerance-by-attenuating-tlr-mediated-signaling
#19
Sanica C Sakharwade, Arunika Mukhopadhaya
Porins can act as pathogen-associated molecular patterns, can be recognized by the host immune system and modulate immune responses. Vibrio choleraeporin OmpU aids in bacterial survival in the human gut by increasing resistance against bile acids and anti-microbial peptides. V. choleraeOmpU is pro-inflammatory in nature. However, interestingly, it can also down-regulate LPS-mediated pro-inflammatory responses. In this study, we have explored how OmpU-pretreatment affects LPS-mediated responses. Our study indicates that OmpU-pretreatment followed by LPS-activation does not induce M2-polarization of macrophages/monocytes...
December 2015: Molecular Immunology
https://www.readbyqxmd.com/read/26309029/the-alpha-melanocyte-stimulating-hormone-suppresses-tlr2-mediated-functional-responses-through-irak-m-in-normal-human-keratinocytes
#20
Sunhyo Ryu, Andrew Johnson, Yoonkyung Park, Beomjoon Kim, David Norris, Cheryl A Armstrong, Peter I Song
Alpha-melanocyte stimulating hormone (α-MSH) is a highly conserved 13-aa neuropeptide derived from pro-opiomelanocortin by post-translational processing, which has been reported to exhibit potent anti-inflammatory activity and a wide range of immunosuppressive activities in the skin. However, the regulatory effect of α-MSH is not completely clear in cutaneous innate immunity. In this study, we investigate the functional regulation of α-MSH in TLR2-mediated inflammatory responses in normal human keratinocytes (HKs)...
2015: PloS One
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