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https://www.readbyqxmd.com/read/28780618/upregulated-irak1-and-irak4-promoting-the-production-of-ifn-%C3%AE-and-il-17-in-behcet-s-disease
#1
Min Sun, Peizeng Yang, Yan Yang, Jian Ye
PURPOSE: To investigate the expression and function of IRAK1 and IRAK4 involved in the development of Behcet's disease. METHODS: Twenty-eight Behcet's patients and thirty-two normal subjects were involved in this study. The mRNA levels of IRAK1 and IRAK4 from active Behcet's patients, inactive Behcet's patients and normal controls were detected using real-time quantitative PCR. CD4(+)T cells were extracted from peripheral blood mononuclear cells of active Behcet's patients and normal controls...
August 5, 2017: International Ophthalmology
https://www.readbyqxmd.com/read/28757610/the-il-1r-tlr-signaling-pathway-is-essential-for-efficient-cd8-t-cell-responses-against-hepatitis-b-virus-in-the-hydrodynamic-injection-mouse-model
#2
Zhiyong Ma, Jia Liu, Weimin Wu, Ejuan Zhang, Xiaoyong Zhang, Qian Li, Gennadiy Zelinskyy, Jan Buer, Ulf Dittmer, Carsten J Kirschning, Mengji Lu
The outcome of hepatitis B viral (HBV) infection is determined by the complex interactions between replicating HBV and the immune system. While the role of the adaptive immune system in the resolution of HBV infection has been studied extensively, the contribution of innate immune mechanisms remains to be defined. Here we examined the role of the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) signaling pathway in adaptive immune responses and viral clearance by exploring the HBV mouse model. Hydrodynamic injection with a replication-competent HBV genome was performed in wild-type mice (WT) and a panel of mouse strains lacking specific innate immunity component expression...
July 31, 2017: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/28750570/identification-of-potential-ibrutinib-combinations-in-hematological-malignancies-using-a-combination-high-throughput-screen
#3
Michael Schaffer, Shalini Chaturvedi, Cuc Davis, Regina Aquino, Emily Stepanchick, Matthias Versele, Yang Liu, Jennifer Yang, Rongzhen Lu, Sriram Balasubramanian
Matrix high-throughput screening (HTS) methods are increasingly employed to rapidly define potential therapeutic drug combinations. We used combination HTS to identify compounds showing synergistic anti-proliferative activity with ibrutinib, an irreversible, small-molecule inhibitor of Bruton's tyrosine kinase. The goal was to identify ibrutinib combinations with maximum synergistic effects in heme malignancy lines, particularly in non-Hodgkin lymphoma including diffuse large B-cell lymphoma (DLBCL). Growth inhibition (GI) was used to measure cell viability; synergy scores characterized strength of synergistic interaction...
July 28, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28739828/mice-bone-marrow-sca-1-cd44-mesenchymal-stem-cells-kill-avirulent-mycobacteria-but-not-mycobacterium-tuberculosis-through-modulation-of-cathelicidin-expression-via-p38-mapk-dependent-pathway
#4
Sumanta Kumar Naik, Avinash Padhi, Geetanjali Ganguli, Srabasti Sengupta, Sanghamitra Pati, Dasarathi Das, Avinash Sonawane
Mycobacterium tuberculosis (Mtb) primarily infects lung macrophages. However, recent study has shown that Mtb also infect and persist in dormant form inside the bone marrow mesenchymal stem cells (BM-MSCs) even after successful antibiotic therapy. However, the mechanism(s) by which Mtb survives in BM-MSCs is still not known. Like macrophages, BM-MSCs do not contain a well-defined endocytic pathway, which is known to play a central role in the clearance of internalized mycobacteria. Here, we studied the fate of virulent and avirulent mycobacteria in Sca-1(+)/CD44(+) BM-MSCs...
July 24, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28726277/aged-garlic-extract-suppresses-inflammation-in-apolipoprotein-e-knockout-mice
#5
Naoaki Morihara, Atsuko Hino, Satomi Miki, Miyuki Takashima, Jun-Ichiro Suzuki
SCOPE: Chronic inflammation plays a major role in the formation and progression of atherosclerotic plaques. To clarify the mode of action of aged garlic extract (AGE) to retard atherosclerosis, we investigated whether AGE suppresses the inflammation in apolipoprotein E-knockout (ApoE-KO) mice. METHODS AND RESULTS: ApoE-KO mice were fed standard diet with or without 3% AGE for 12 weeks. AGE feeding inhibited the progression of atherosclerotic lesion by 27% and reduced the level of C-reactive protein (CRP) and thromboxane B2 (TXB2 ), a marker of platelet activation, in serum by 39% and 33%, respectively, compared to ApoE-KO mice without AGE treatment...
July 20, 2017: Molecular Nutrition & Food Research
https://www.readbyqxmd.com/read/28702714/immunodeficiency-in-two-female-patients-with-incontinentia-pigmenti-with-heterozygous-nemo-mutation-diagnosed-by-lps-unresponsiveness
#6
Hidenori Ohnishi, Yuka Kishimoto, Tomohide Taguchi, Norio Kawamoto, Mina Nakama, Tomoki Kawai, Manabu Nakayama, Osamu Ohara, Kenji Orii, Toshiyuki Fukao
PURPOSE: Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) is caused by mutations in the NF-κB essential modulator (NEMO) or NF-κB inhibitor, alpha (IKBA) genes. A heterozygous NEMO mutation causes incontinentia pigmenti (IP) in females, while a hemizygous hypomorphic mutation of NEMO causes EDA-ID in males. In general, immunodeficiency is not shown in IP patients. Here, we investigated two female patients with IP and immunodeficiency. METHODS: The patients were initially suspected to have IRAK4 deficiency and Mendelian susceptibility to mycobacterial disease, respectively, because of recurrent pneumonia with delayed umbilical cord detachment or disseminated mycobacterial infectious disease...
July 12, 2017: Journal of Clinical Immunology
https://www.readbyqxmd.com/read/28684198/flow-cytometry-based-diagnosis-of-primary-immunodeficiency-diseases
#7
REVIEW
Hirokazu Kanegane, Akihiro Hoshino, Tsubasa Okano, Takahiro Yasumi, Taizo Wada, Hidetoshi Takada, Satoshi Okada, Motoi Yamashita, Tzu-Wen Yeh, Ryuta Nishikomori, Masatoshi Takagi, Kohsuke Imai, Hans D Ochs, Tomohiro Morio
Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited diseases of the immune system. The definite diagnosis of PID is ascertained by genetic analysis; however, this takes time and is costly. Flow cytometry provides a rapid and highly sensitive tool for diagnosis of PIDs. Flow cytometry can evaluate specific cell populations and subpopulations, cell surface, intracellular and intranuclear proteins, biologic effects associated with specific immune defects, and certain functional immune characteristics, each being useful for the diagnosis and evaluation of PIDs...
July 3, 2017: Allergology International: Official Journal of the Japanese Society of Allergology
https://www.readbyqxmd.com/read/28659605/mmm-derived-lipid-associated-membrane-proteins-activate-il-1%C3%AE-production-through-the-nf-%C3%AE%C2%BAb-pathway-via-tlr2-myd88-and-irak4
#8
Yang Wang, Qi Wang, Yuan Li, Ying Chen, Jiari Shao, Nwankpa Nick, Chunyan Li, Jiuqing Xin
Mycoplasma mycoides subsp.mycoides (Mmm) is a pathogen that causes pneumonia, otitis media, and arthritis in young calves. Its pathogenesis is attributed in part to excessive immune responses. Mmm-derived lipid-associated membrane proteins (LAMPs) are potent inducers of the host innate immune system; however, interactions between Mmm-derived LAMPs as pathogenic agents, toll-like receptors (TLRs), and the signaling pathways responsible for activating inflammation and nuclear factor (NF)-κB have not been fully elucidated...
June 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28646802/dampness-can-promote-the-influenza-a-virus-and-worsen-its-prognosis-by-upregulating-the-tlr7-signaling-pathway
#9
Deng Li, Xu Huachong, Pang Peng, Zheng Ke, Nie Jiao, Wu Xianlin, Yu Bin, Chen Jia, Chen Xiaoyin
Context • Outbreaks of the influenza A virus (IAV) are increasingly recognized as a global public health issue, affecting a large proportion of the world's population. A number of studies have provided epidemiologic evidence that dampness and mold are consistently associated with multiple allergic and respiratory effects, but they focused on dampness-related pathogenic microorganisms leading to allergy rather than the dampness itself. Objective • The current study intended to examine the effects of a damp environment on the promotion of the IAV and determine the adverse effects on its prognosis through upregulation of the toll-like receptor 7 (TLR7)-signaling pathway in the lung...
June 23, 2017: Alternative Therapies in Health and Medicine
https://www.readbyqxmd.com/read/28556291/prenatal-phthalate-exposure-and-altered-patterns-of-dna-methylation-in-cord-blood
#10
Olivia Solomon, Paul Yousefi, Karen Huen, Robert B Gunier, Maria Escudero-Fung, Lisa F Barcellos, Brenda Eskenazi, Nina Holland
Epigenetic changes such as DNA methylation may be a molecular mechanism through which environmental exposures affect health. Phthalates are known endocrine disruptors with ubiquitous exposures in the general population including pregnant women, and they have been linked with a number of adverse health outcomes. We examined the association between in utero phthalate exposure and altered patterns of cord blood DNA methylation in 336 Mexican-American newborns. Concentrations of 11 phthalate metabolites were analyzed in maternal urine samples collected at 13 and 26 weeks gestation as a measure of fetal exposure...
July 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28536249/bronchial-inflammation-and-bacterial-load-in-stable-copd-is-associated-with-tlr4-overexpression
#11
Antonino Di Stefano, Fabio L M Ricciardolo, Gaetano Caramori, Ian M Adcock, Kian Fan Chung, Peter J Barnes, Paola Brun, Andrea Leonardi, Filippo Andò, Davide Vallese, Isabella Gnemmi, Luisella Righi, Francesco Cappello, Bruno Balbi
Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain (NOD)-like receptors (NLRs) are two major forms of innate immune sensors but their role in the immunopathology of stable chronic obstructive pulmonary disease (COPD) is incompletely studied. Our objective here was to investigate TLR and NLR signalling pathways in the bronchial mucosa in stable COPD.Using immunohistochemistry, the expression levels of TLR2, TLR4, TLR9, NOD1, NOD2, CD14, myeloid differentiation primary response gene 88 (MyD88), Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP), and the interleukin-1 receptor-associated kinases phospho-IRAK1 and IRAK4 were measured in the bronchial mucosa of subjects with stable COPD of different severity (n=34), control smokers (n=12) and nonsmokers (n=12)...
May 2017: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
https://www.readbyqxmd.com/read/28512203/the-mechanism-of-activation-of-irak1-and-irak4-by-interleukin-1-and-toll-like-receptor-agonists
#12
COMPARATIVE STUDY
Stefan Vollmer, Sam Strickson, Tinghu Zhang, Nathanael Gray, Katherine L Lee, Vikram R Rao, Philip Cohen
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...
June 6, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28503543/irak4-deficiency-in-a-patient-with-recurrent-pneumococcal-infections-case-report-and-review-of-the-literature
#13
Karina Gobin, Mary Hintermeyer, Bertrand Boisson, Maya Chrabieh, Pegah Gandil, Ann Puel, Capucine Picard, Jean-Laurent Casanova, John Routes, James Verbsky
Primary immunodeficiencies are genetic defects of the innate or adaptive immune system, resulting in a propensity to infections. The innate immune system is the first line of defense against pathogens and is critical to recognize microbes and start the inflammatory cascade. Sensing of microbes occurs by a number of pathogen-recognition receptors, resulting in the activation of inflammatory signal transduction pathways, such as the activation of NF-κB. Herein, we describe a case of IRAK4 deficiency, a key signal transduction molecule of toll-like and IL-1 receptors...
2017: Frontiers in Pediatrics
https://www.readbyqxmd.com/read/28501511/identification-of-quinazoline-based-inhibitors-of-irak4-for-the-treatment-of-inflammation
#14
Graham F Smith, Michael D Altman, Brian Andresen, James Baker, Jason D Brubaker, Hongmin Chen, Yiping Chen, Matthew Childers, Anthony Donofrio, Heidi Ferguson, Christian Fischer, Thierry O Fischmann, Craig Gibeau, Alexander Hicks, Sue Jin, Sam Kattar, Melanie A Kleinschek, Erica Leccese, Charles Lesburg, Chaomin Li, Jongwon Lim, Duan Liu, John K F Maclean, Faruk Mansoor, Lilly Y Moy, Erin F Mulrooney, Antoaneta S Necheva, Jeremy Presland, Larissa Rakhilina, Ruojing Yang, Luis Torres, Jie Zhang-Hoover, Alan Northrup
Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity...
June 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28500047/self-reactive-vh4-34-expressing-igg-b-cells-recognize-commensal-bacteria
#15
Jean-Nicolas Schickel, Salomé Glauzy, Yen-Shing Ng, Nicolas Chamberlain, Christopher Massad, Isabelle Isnardi, Nathan Katz, Gulbu Uzel, Steven M Holland, Capucine Picard, Anne Puel, Jean-Laurent Casanova, Eric Meffre
The germline immunoglobulin (Ig) variable heavy chain 4-34 (VH4-34) gene segment encodes in humans intrinsically self-reactive antibodies that recognize I/i carbohydrates expressed by erythrocytes with a specific motif in their framework region 1 (FWR1). VH4-34-expressing clones are common in the naive B cell repertoire but are rarely found in IgG memory B cells from healthy individuals. In contrast, CD27(+)IgG(+) B cells from patients genetically deficient for IRAK4 or MYD88, which mediate the function of Toll-like receptors (TLRs) except TLR3, contained VH4-34-expressing clones and showed decreased somatic hypermutation frequencies...
July 3, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28498658/discovery-of-clinical-candidate-1-2s-3s-4s-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl-methoxy-7-methoxyisoquinoline-6-carboxamide-pf-06650833-a-potent-selective-inhibitor-of-interleukin-1-receptor-associated-kinase-4-irak4-by-fragment-based-drug-design
#16
Katherine L Lee, Catherine M Ambler, David R Anderson, Brian P Boscoe, Andrea G Bree, Joanne I Brodfuehrer, Jeanne S Chang, Chulho Choi, Seungwon Chung, Kevin J Curran, Jacqueline E Day, Christoph M Dehnhardt, Ken Dower, Susan E Drozda, Richard K Frisbie, Lori K Gavrin, Joel A Goldberg, Seungil Han, Martin Hegen, David Hepworth, Heidi R Hope, Satwik Kamtekar, Iain C Kilty, Arthur Lee, Lih-Ling Lin, Frank E Lovering, Michael D Lowe, John P Mathias, Heidi M Morgan, Elizabeth A Murphy, Nikolaos Papaioannou, Akshay Patny, Betsy S Pierce, Vikram R Rao, Eddine Saiah, Ivan J Samardjiev, Brian M Samas, Marina W H Shen, Julia H Shin, Holly H Soutter, Joseph W Strohbach, Peter T Symanowicz, Jennifer R Thomason, John D Trzupek, Richard Vargas, Fabien Vincent, Jiangli Yan, Christoph W Zapf, Stephen W Wright
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40)...
June 14, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28408332/molecular-cloning-structural-modeling-and-expression-analysis-of-myd88-and-irak4-of-golden-pompano-trachinotus-ovatus
#17
Zhitao Qi, Baobao Sun, Qihuan Zhang, Fancui Meng, Qiaoqing Xu, Youchuan Wei, Qian Gao
MyD88 and IRAK4 are important components of TLR signaling pathways. However, information about MyD88 and IRAK4 is vacant in golden pompano (Trachinotus ovatus), a marine teleost with great commercial value. Thus, in this study the full lengths of trMyD88 and trIRAK4 were cloned from golden pompano using RT-PCR and RACE-PCR methods. trMyD88 was 1213 bp in length, encoding a putative protein of 288 amino acids (aa), consisting of a 99 aa of death domain at its N-terminal and a 137 aa of the TIR domain at its C-terminal...
September 2017: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/28404732/roles-of-the-traf6-and-pellino-e3-ligases-in-myd88-and-rankl-signaling
#18
Sam Strickson, Christoph H Emmerich, Eddy T H Goh, Jiazhen Zhang, Ian R Kelsall, Thomas Macartney, C James Hastie, Axel Knebel, Mark Peggie, Francesco Marchesi, J Simon C Arthur, Philip Cohen
It is widely accepted that the essential role of TRAF6 in vivo is to generate the Lys63-linked ubiquitin (K63-Ub) chains needed to activate the "master" protein kinase TAK1. Here, we report that TRAF6 E3 ligase activity contributes to but is not essential for the IL-1-dependent formation of K63-Ub chains, TAK1 activation, or IL-8 production in human cells, because Pellino1 and Pellino2 generate the K63-Ub chains required for signaling in cells expressing E3 ligase-inactive TRAF6 mutants. The IL-1-induced formation of K63-Ub chains and ubiquitylation of IRAK1, IRAK4, and MyD88 was abolished in TRAF6/Pellino1/Pellino2 triple-knockout (KO) cells, but not in TRAF6 KO or Pellino1/2 double-KO cells...
April 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28378188/apigenin-suppresses-the-senescence-associated-secretory-phenotype-and-paracrine-effects-on-breast-cancer-cells
#19
Kevin M Perrott, Christopher D Wiley, Pierre-Yves Desprez, Judith Campisi
Apigenin (4',5,7,-trihydroxyflavone) is a flavonoid found in certain herbs, fruits, and vegetables. Apigenin can attenuate inflammation, which is associated with many chronic diseases of aging. Senescent cells-stressed cells that accumulate with age in mammals-display a pro-inflammatory senescence-associated secretory phenotype (SASP) that can drive or exacerbate several age-related pathologies, including cancer. Flavonoids, including apigenin, were recently shown to reduce the SASP of a human fibroblast strain induced to senesce by bleomycin...
April 2017: GeroScience
https://www.readbyqxmd.com/read/28363843/toll-like-receptor-9-mediates-paraquat-induced-acute-lung-injury-an-in-vitro-and-in-vivo-study
#20
Haitao Shen, Na Wu, Yu Wang, Lichun Zhang, Xiao Hu, Zhiguang Chen, Min Zhao
AIMS: This study aimed to investigate the role of Toll-like receptor 9 in paraquat-induced acute lung injury (ALI). MAIN METHODS: For in vivo study,C57BL mice were randomly assigned into the vehicle control group, paraquat group, paraquat + TLR9 antagonist (ODN2088) group, and TLR9 antagonist (ODN2088) group (n=36 per group). After paraquat 30mg/kg ip for 2, 24 and 48h, serum samples and lung tissues were collected to evaluate ALI and TLR9 signaling by lung injury score, protein levels of TLR9, MyD88, p-IRAK4, p-p65, and serum TNF-α and IL-1β levels...
June 1, 2017: Life Sciences
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