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Goutham Pattabiraman, Michael Murphy, Federica Agliano, Keaton Karlinsey, Andrei E Medvedev
IL-1 receptor-associated kinase (IRAK) 4 is a central enzyme of the TLR pathways. This study tested the hypothesis that IRAK4 kinase activity is prerequisite for regulating innate immunity during infections with intracellular bacteria. To this end, we analyzed responses of macrophages obtained from mice expressing wild-type (WT) IRAK4 or its kinase-inactive K213M mutant (IRAK4KI ) upon infection with intracellular bacteria Listeria monocytogenes or Mycobacterium smegmatis. In contrast to robust induction of cytokines by macrophages expressing kinase-sufficient IRAK4, IRAK4KI macrophages expressed decreased TNF-α, IL-6, IL-1β, and C-C motif chemokine ligand 5 upon infection with L...
May 11, 2018: Journal of Leukocyte Biology
Mona M Hosseini, Stephen E Kurtz, Sherif Abdelhamed, Shawn Mahmood, Monika A Davare, Andy Kaempf, Johannes Elferich, Jason E McDermott, Tao Liu, Samuel H Payne, Ujwal Shinde, Karin D Rodland, Motomi Mori, Brian J Druker, Jack W Singer, Anupriya Agarwal
Interleukin-1 receptor-associated kinase 1 (IRAK1), an essential mediator of innate immunity and inflammatory responses, is constitutively active in multiple cancers. We evaluated the role of IRAK1 in acute myeloid leukemia (AML) and assessed the inhibitory activity of multikinase inhibitor pacritinib on IRAK1 in AML. We demonstrated that IRAK1 is overexpressed in AML and provides a survival signal to AML cells. Genetic knockdown of IRAK1 in primary AML samples and xenograft model showed a significant reduction in leukemia burden...
March 29, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Olfat Gamil Shaker, Noha Ahmed El Boghdady, Abeer El-Dessouki El Sayed
BACKGROUND/AIMS: Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting up to 1% of the population worldwide. The aim of the present study was to investigate whether miRNA-146a rs2910164, miRNA-499 rs3746444, IRAK1 rs3027898 and PADI4 rs1748033 polymorphisms are associated with susceptibility to RA in Egyptians and whether they influence disease severity and activity. METHODS: The study was performed on 104 unrelated RA patients and 112 healthy subjects...
May 3, 2018: Cellular Physiology and Biochemistry
Huoru Zhang, Yan Zhang, Yong-Fei Wang, David Morris, Nattiya Hirankarn, Yujun Sheng, Jiangshan Shen, Hai-Feng Pan, Jing Yang, Sen Yang, Yong Cui, Dong-Qing Ye, Timothy J Vyse, Xuejun Zhang, Yu Lung Lau, Wanling Yang
BACKGROUND: Systemic lupus erythematous (SLE) is a complex autoimmune disease with female predominance, particularly affecting those of childbearing age. We performed analysis of three genome-wide genotyping datasets of populations of both Chinese and European origin. METHODS: This study involved 5695 cases and 10,357 controls in the discovery stage. The lead signal on chromosome X was followed by replication in three additional Asian cohorts, with 2300 cases and 4244 controls in total...
May 3, 2018: Arthritis Research & Therapy
Hua Wang, Pan Hao, Hu Zhang, Cuiping Xu, Junyan Zhao
This study was aimed to research the effect of miR-223 on the inflammatory responses induced by lipopolysaccharide (LPS) in nucleus pulposus (NP) cells of rat intervertebral disc. Isolated rat NP cells were induced by LPS. Reverse transcriptase quantitative real-time polymerase chain reaction was used to detect gene expression. To detect protein expression, Western blot and enzyme-linked immunosorbent assay experiments were applied. The putative targeting relationship between miR-223 and Irak1 was determined using dual-luciferase reporter gene assay...
April 29, 2018: IUBMB Life
Qiming Hu, Jiacheng Song, Bo Ding, Yugui Cui, Jiale Liang, Suping Han
Cervical cancer is the third most common type of cancer in women, and microRNAs play an important role in this type of cancer. The elevated expression of miR-146a is involved in the pathogenesis of cancers generally, but its role in cervical cancer has not been fully elucidated. In the present study, we assessed the expression of miR-146a in G>C polymorphisms and confirmed that the overexpression of miR-146a promoted cervical cancer cell viability. The recombinant expression plasmids pre-miR-146a-G or pre-miR-146a-C including single nucleotide polymorphisms (SNP) were successfully constructed...
April 23, 2018: Oncology Reports
Liwei Zhao, Jian Li, Shiyun Huang
BACKGROUND: Immune intolerance of the fetal-placental unit may be a contributing cause of unexplained recurrent spontaneous abortion (URSA). OBJECTIVES: This study is to investigate the relevance of the miR-146a-5p/IFN-γ pathway to URSA. MATERIAL AND METHODS: Quantitative real-time RT-PCR and western blot were performed to compare the levels of miR-146a-5p, IFN-γ, IRAK1, and TRAF6 in the deciduae of URSA (n=29) and healthy women (n=35) after an elective abortion...
March 2018: Annals of Clinical and Laboratory Science
Fiachra Humphries, Ronan Bergin, Ruaidhri Jackson, Nezira Delagic, Bingwei Wang, Shuo Yang, Alice V Dubois, Rebecca J Ingram, Paul N Moynagh
The NLRP3 inflammasome has an important function in inflammation by promoting the processing of pro-IL-1β and pro-IL-18 to their mature bioactive forms, and by inducing cell death via pyroptosis. Here we show a critical function of the E3 ubiquitin ligase Pellino2 in facilitating activation of the NLRP3 inflammasome. Pellino2-deficient mice and myeloid cells have impaired activation of NLRP3 in response to toll-like receptor priming, NLRP3 stimuli and bacterial challenge. These functions of Pellino2 in the NLRP3 pathway are dependent on Pellino2 FHA and RING-like domains, with Pellino2 promoting the ubiquitination of NLRP3 during the priming phase of activation...
April 19, 2018: Nature Communications
Limin Liu, Chong Wan, Wei Zhang, Longfei Guan, Guoxiong Tian, Fang Zhang, Wenjun Ding
Exposure to particulate matter (PM) leads to kinds of cardiopulmonary diseases, such as asthma, COPD, arrhythmias, lung cancer, etc., which are related to PM-induced inflammation. We have found that PM2.5 (aerodynamics diameter <2.5 µm) exposure induces inflammatory response both in vivo and in vitro. Since the toxicity of PM is tightly associated with its size and components, PM1 (aerodynamics diameter <1.0 µm) is supposed to be more toxic than PM2.5 . However, the mechanism of PM1 -induced inflammation is not clear...
April 18, 2018: Environmental Toxicology
Z-X Sheng, H Yao, Z-Y Cai
OBJECTIVE: MicroRNAs (miRNAs) are now recognized as important regulators of gene expression. The aim of the study was to investigate the role of miR-146b-5p in the TLR4 pathway and provide the basis for the treatment of lupus nephritis. MATERIALS AND METHODS: The glomerular mesangial cells were cultured in vitro and divided into 3 groups: control group, a group of miR-146b-5p mimic added, and a group of miR-146b-5p inhibitor added. The levels of IL-6 and IL-8 in the cell culture supernatant of the three groups were detected by ELISA...
March 2018: European Review for Medical and Pharmacological Sciences
Si Chen, Wenwei Yin, Kun Bi, Bin Lu
The aim of the present study was to investigate the function and mechanism of microRNA‑497 (miRNA/miR‑149) in the regulation of cerebral infarction. In patients with cerebral infarction, the serum of microRNA‑497 expression was upregulated compared with that in healthy controls. In N2A cells, overexpression of miR‑497 induced cell proliferation, decreased apoptosis and caspase‑3 and caspase‑9 activities, and suppressed Bax protein expression compared with that in the negative control group. Overexpression of miR‑497 reduced inflammation factors, and suppressed the Toll‑like receptor 4 (TLR4), myeloid differentiation primary response protein MyD88 (MyD88) and nuclear factor‑κB (NF‑κB) protein expression of the N2A cells...
April 3, 2018: International Journal of Molecular Medicine
J Mascarenhas, E Virtgaym, M Stal, H Blacklock, A T Gerds, R Mesa, P Ganly, D Snyder, I Tabbara, D Tremblay, E Moshier
Myelofibrosis (MF) is a chronic yet progressive myeloid neoplasm in which only a minority of patients undergo curative therapy, hematopoietic stem cell transplantation. Ruxolitinib, a JAK1/2 inhibitor, is the lone therapy approved for MF, offering a clear symptom and spleen benefit at the expense of treatment-related cytopenias. Pacritinib (PAC), a multi-kinase inhibitor with specificity for JAK2, FLT3, and IRAK1 but sparing JAK1, has demonstrated clinical activity in MF with minimal myelosuppression. Due to an FDA-mandated full clinical hold, the randomized phase 3 PERSIST trials were abruptly stopped and PAC was immediately discontinued for all patients...
April 3, 2018: Annals of Hematology
Zhou Zhou, Zhiqiang Tian, Mengjie Zhang, Yuxun Zhang, Bing Ni, Fei Hao
Systemic lupus erythematosus (SLE) is a typical autoimmune disease. Genome-wide analyses have revealed that interleukin-1 receptor-associated kinase 1 (IRAK1) is associated with susceptibility to SLE. Our previous study investigated the role of IRAK1 in nuclear factor-κB (NF-κB)-related pathways in a mouse model of lupus. In this study, we aimed to further explore the etiological role of IRAK1. The gene expression and phosphorylation of IRAK1 in CD4+ T cells from lupus patients and healthy controls were examined by quantitative reverse transcription-polymerase chain reaction and western blotting, respectively...
April 3, 2018: Immunological Investigations
Hongwei Wang, Yibo Zhang, Xiaojin Wu, Yufeng Wang, Hanwei Cui, Xinxin Li, Jianying Zhang, Norman Tun, Yong Peng, Jianhua Yu
Natural killer (NK) cells are one group of innate lymphocytes that are important for host defense against malignancy and viruses. MicroRNAs (miRNAs) play a critical role in regulating responses of immune cells including NK cells. Accumulating evidence suggests that miR-146a is involved in the regulation of immune responses. However, the mechanism by which miR-146a regulates NK cell function is largely unknown. In the current study, we found that miR-146a intrinsically regulated NK cell function. Forced overexpression of miR-146a decreased IFN-γ production, whereas downregulation of miR-146a by anti-miR-146a significantly enhanced IFN-γ production in the human NK-92 cell line and primary human NK cells upon stimulation with IL-12 or co-stimulation with IL-12 and IL-18...
2018: Frontiers in Immunology
Pietro Presicce, Chan-Wook Park, Paranthaman Senthamaraikannan, Sandip Bhattacharyya, Courtney Jackson, Fansheng Kong, Cesar M Rueda, Emily DeFranco, Lisa A Miller, David A Hildeman, Nathan Salomonis, Claire A Chougnet, Alan H Jobe, Suhas G Kallapur
Neutrophil infiltration of the chorioamnion-decidua tissue at the maternal-fetal interface (chorioamnionitis) is a leading cause of prematurity, fetal inflammation, and perinatal mortality. We induced chorioamnionitis in preterm rhesus macaques by intraamniotic injection of LPS. Here, we show that, during chorioamnionitis, the amnion upregulated phospho-IRAK1-expressed neutrophil chemoattractants CXCL8 and CSF3 in an IL-1-dependent manner. IL-1R blockade decreased chorio-decidua neutrophil accumulation, neutrophil activation, and IL-6 and prostaglandin E2 concentrations in the amniotic fluid...
March 22, 2018: JCI Insight
Shuying He, Weihong Guo, Feihong Deng, Kequan Chen, Yonghong Jiang, Minyu Dong, Liang Peng, Xueqing Chen
Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, and precision therapeutic will be a benefit for the NAFLD regression. In this study, we observed low microRNA 146 b (miR-146 b) expression in NAFLD mice model induced by methionine-choline-deficient diet (MCD) compared with control group. Furthermore, miR-146b-/- mice induced MCD exhibited severe liver steatosis and hepatitis. A bio-distribution study showed that novel Lactosylated PDMAEMA nanoparticles effectively targeted hepatocytes Lac-PDMAEMA...
March 21, 2018: Artificial Cells, Nanomedicine, and Biotechnology
Quan-Bo Zhang, Yu-Feng Qing, Cong-Cong Yin, Li Zhou, Xian-Shuang Liu, Qing-Sheng Mi, Jing-Guo Zhou
BACKGROUND: MicroRNAs (miRNAs) serve as important regulators of inflammatory and immune responses and are implicated in several immune disorders including gouty arthritis. The expression of miR-146a is upregulated in the peripheral blood mononuclear cells of patients with inter-critical gout when compared to normouricemic and hyperuricemic controls and those patients with acute gout flares. However, the role of miR-146a in the development of gout remains unknown. Here, we used miR-146a knockout (KO) mice to test miR-146a function in a monosodium urate (MSU)-induced gouty arthritis model...
March 15, 2018: Arthritis Research & Therapy
Bo Chu, Yadong Zhou, Heng Zhai, Lei Li, Li Sun, Yun Li
MicroRNA-146a (miR-146a) is reportedly implicated in the pathogenesis of ischemia-reperfusion (I/R) injury; however, its role in cerebral I/R injury is unclear and requires further investigation. In this study, cerebral I/R injury was established in mice via middle cerebral artery occlusion, and the expression of miR-146a was detected in the brain tissue via quantitative real-time PCR. We found that the expression of miR-146a was upregulated. Furthermore, the endogenous miR-146a was antagonized by its specific inhibitor...
March 5, 2018: Canadian Journal of Physiology and Pharmacology
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 (TIC) within the tumor bulk. Therefore, targeting liver TICs 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...
May 1, 2018: Cancer Research
(no author information available yet)
[This corrects the article on p. 8025 in vol. 12, PMID: 29184402.].
2018: International Journal of Nanomedicine
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