Guo L, etal., Cell Death Dis. 2015 Oct 29;6:e1949. doi: 10.1038/cddis.2015.212.
The activation of Toll-like receptor 4 (TLR4) signaling has an important role in promoting lipid accumulation and pro-inflammatory effects in vascular smooth muscle cells (VSMCs), which facilitate atherosclerosis development and progression. Previous studies have demonstrated that excess lipid accu
mulation in VSMCs is due to an inhibition of the expression of ATP-binding cassette transporter A1 (ABCA1), an important molecular mediator of lipid efflux from VSMCs. However, the underlying molecular mechanisms of this process are unclear. The purpose of this study was to disclose the underlying molecular mechanisms of TLR4 signaling in regulating ABCA1 expression. Primary cultured VSMCs were stimulated with 50 mug/ml oxidized low-density lipoprotein (oxLDL). We determined that enhancing TLR4 signaling using oxLDL significantly downregulated ABCA1 expression and induced lipid accumulation in VSMCs. However, TLR4 knockout significantly rescued oxLDL-induced ABCA1 downregulation and lipid accumulation. In addition, IL-1R-associated kinase 1 (IRAK1) was involved in the effects of TLR4 signaling on ABCA1 expression and lipid accumulation. Silencing IRAK1 expression using a specific siRNA reversed TLR4-induced ABCA1 downregulation and lipid accumulation in vitro. These results were further confirmed by our in vivo experiments. We determined that enhancing TLR4 signaling by administering a 12-week-long high-fat diet (HFD) to mice significantly increased IRAK1 expression, which downregulated ABCA1 expression and induced lipid accumulation. In addition, TLR4 knockout in vivo reversed the effects of the HFD on IRAK1 and ABCA1 expression, as well as on lipid accumulation. In conclusion, IRAK1 is involved in TLR4-mediated downregulation of ABCA1 expression and lipid accumulation in VSMCs.
Xia P, etal., Immunol Lett. 2012 Dec 17;148(2):151-62. doi: 10.1016/j.imlet.2012.09.004. Epub 2012 Sep 24.
Psoriasis is a common chronic inflammatory skin disorder with dysregulation of miRNAs. The expression pattern of miR-146a and target gene IRAK1 in lesions and PBMCs of plaque psoriasis remains unclear. In our study, we found the expression of miR-146a was up-re
gulated both in lesions and PBMCs of psoriatic patients, and positively correlated with IL-17 expression, whereas the target gene IRAK1 expression was expressed differentially in lesions and peripheral blood. Inability of miR-146a inhibiting target gene IRAK1 may contribute to the persistent inflammation in lesions of psoriasis.
Wee ZN, etal., Nat Commun. 2015 Oct 27;6:8746. doi: 10.1038/ncomms9746.
Metastatic tumour recurrence due to failed treatments remains a major challenge of breast cancer clinical management. Here we report that interleukin-1 receptor-associated kinase 1 (IRAK1) is overexpressed in a subset of breast cancers, in particular triple-nega
tive breast cancer (TNBC), where it acts to drive aggressive growth, metastasis and acquired resistance to paclitaxel treatment. We show that IRAK1 overexpression confers TNBC growth advantage through NF-kappaB-related cytokine secretion and metastatic TNBC cells exhibit gain of IRAK1 dependency, resulting in high susceptibility to genetic and pharmacologic inhibition of IRAK1. Importantly, paclitaxel treatment induces strong IRAK1 phosphorylation, an increase in inflammatory cytokine expression, enrichment of cancer stem cells and acquired resistance to paclitaxel treatment. Pharmacologic inhibition of IRAK1 is able to reverse paclitaxel resistance by triggering massive apoptosis at least in part through inhibiting p38-MCL1 pro-survival pathway. Our study thus demonstrates IRAK1 as a promising therapeutic target for TNBC metastasis and paclitaxel resistance.
Li C, etal., J Infect Dev Ctries. 2015 Jul 4;9(6):614-23. doi: 10.3855/jidc.6776.
INTRODUCTION: Infection of pathogenic microorganisms is an important reason for autoimmune diseases (ADs). Interleukin-1 (IL-1) receptor-associated kinase-1 (IRAK1) is a key mediator in infection immunity, while the gene of IRAK1
span> is recognized as a risk gene in ADs. Three single nucleotide polymorphisms (SNPs) in IRAK1 (rs3027898, rs1059702, rs1059703) are considered to be associated with ADs risk. However, the results are conflicting. We conducted this study to get more precise estimations. METHODOLOGY: PubMed, OvidSP, and CNKI databases (published prior to August 2014) were searched, and data was extracted from eligible studies. The procedure of statistical analysis was performed using STATA 12.0 software. A random effect model or fixed effect model was chosen based on the between-study heterogeneities. RESULTS: Of the studies involved, 11 studies included 10,705 cases (9,865 controls) for rs3027898, 9 studies included 15,005 cases (14,997 controls) for rs1059702, and 7 studies included 8,115 cases (6,815 controls) for rs1059703. Overall, the results showed that there were significant associations with ADs risk in three genetic models for rs3027898 and in four genetic models for rs1059702, but in neither model for rs1059703. Moreover, in stratified analyses, different extents of associations were found in some different genetic models for all three SNPs. CONCLUSION: Our data demonstrated that these three SNPs (rs3027898, rs1059702, rs1059703) in IRAK1 were associated with ADs risk.
BACKGROUND: Severe invasive pneumococcal disease (SIPD) has high morbidity and mortality, conditioned by pneumococcus and host factors, such as Toll-like receptors and their Toll-IL1R common signaling pathway. The objectives of this study are (1) to correlate single nucleotide polymorphisms (SNPs) i
nvolved in some Toll-IL1R signaling pathway proteins (IRAK1, IRAK4, IRAKM and MyD88) with SIPD by comparing patients versus healthy controls. (2) To determine whether these SNPs influence SIPD outcome. METHODS: Case-control prospective observational study: 60 pediatric patients with IPD and systemic inflammatory response syndrome, and 120 healthy volunteers. Well-known immunodeficiencies were excluded. INDEPENDENT VARIABLES: SNPs genotypes and alleles. Other variables: demographic, previous infections, and clinical, analytical and microbiological evolution data. RESULTS: We have detected significant disequilibrium of SNPs frequencies between SIPD patients and controls in rs1059701-CC (IRAK1; P = 0.0067), rs4251513-CC (IRAK4; P < 0.0001), rs1461567-T (IRAK4; P = 0.0158) and rs6853-AA (MyD88; P < 0.0001). SIPD patients showed significant association between: leukocytosis > 15,000/mmc and rs1059702-nonTT (IRAK1; P = 0.0460), pleuropneumonia and rs1624395-G (IRAKM; P = 0.0147), and rs1370128-C (IRAKM; P = 0.0055), sequelae, and rs4251513-nonGG (IRAK4; P = 0.0055), death and rs6853-nonAA (P = 0.0054) and rs6853-G (P = 0.0065; MyD88). CONCLUSIONS: This is the first study to show an association between SNPs in IRAK1, IRAK4 and MyD88, and the presence of SIPD. Our data showed that some SNPs may lead to a higher risk of developing SIPD while other are related with the outcome in SIPD patients. Following PIRO score (predisposition, insult, response, organ dysfunction), identifying SNPs predisposing to infectious diseases, such as SIPD might help stratify patients with severe infectious diseases and design specific treatments.
Thomas JA, etal., Am J Physiol Heart Circ Physiol. 2003 Aug;285(2):H597-606.
Myocardial contractile dysfunction accompanies both systemic and cardiac insults. Septic shock and burn trauma can lead to reversible contractile deficits, whereas ischemia and direct inflammation of the heart can precipitate transient or permanent impairments in contractility. Many of the insults t
hat trigger contractile dysfunction also activate the innate immune system. Activation of the innate immune response to infection is coordinated by the conserved Toll/interleukin-1 (IL-1) signal transduction pathway. Interestingly, components of this pathway are also expressed in normal and failing hearts, although their function is unknown. The hypotheses that Toll/IL-1 signaling occurs in the heart and that intact pathway function is required for contractile dysfunction after different insults were tested. Results from these experiments demonstrate that lipopolysaccharides (LPS) activate Toll/IL-1 signaling and IL-1 receptor-associated kinase-1 (IRAK1), a critical pathway intermediate in the heart, indicating that the function of this pathway is not limited to immune system tissues. Moreover, hearts lacking IRAK1 exhibit impaired LPS-triggered downstream signal transduction. Hearts from IRAK1-deficient mice also resist acute LPS-induced contractile dysfunction. Finally, IRAK1 inactivation enhances survival of transgenic mice that develop severe myocarditis and lethal heart failure. Thus the Toll/IL-1 pathway is active in myocardial tissue and interference with pathway function, through IRAK1 inactivation, may represent a novel strategy to protect against cardiac contractile dysfunction.
Liu Y, etal., Biomed Res Int. 2022 May 13;2022:6584645. doi: 10.1155/2022/6584645. eCollection 2022.
INTRODUCTION: Atherosclerosis (AS) is a chronic inflammatory disease characterized by lipid metabolism disorder and vascular endothelial damage. Albiflorin (AF) has been certified to be effective in the therapy of certain inflammatory diseases, while the therapeutic effect and mechanism o
f AF on AS have not been fully elucidated. Material and Methods. Model cells for AS were created by inducing oxidized low-density lipoprotein (Ox-LDL) in human umbilical vein endothelial cells (HUVECs). After processing with AF and interleukin-1 receptor-associated kinase 1- (IRAK1-) overexpressed plasmid, cell viability was assessed by CCK-8; cholesterol efflux was tested using liquid scintillation counter; IL-6 and TNF-α levels were determined with ELISA kits; ROS and apoptosis were confirmed using Flow cytometry. Besides, IRAK1-TAK1 pathway and apoptosis- and mitochondrial fusion-related proteins were monitored with western blotting analysis. RESULTS: Our results verified that AF could not only dramatically accelerate viability and cholesterol efflux but also attenuate inflammation, ROS production, and apoptosis in Ox-LDL-induced HUVECs. Meanwhile, AF could prominently prevent the activation of IRAK1-TAK1 pathway, downregulate apoptosis-related proteins, and upregulate mitochondrial fusion-related proteins in Ox-LDL-induced HUVECs. Moreover, we testified that IRAK1 overexpression memorably could reverse suppression of AF on inflammation, apoptosis, and IRAK1-TAK1 pathway and enhancement of AF on viability, cholesterol efflux, and mitochondrial fusion in Ox-LDL-induced HUVECs. CONCLUSIONS: By blocking the IRAK1/TAK1 pathway, AF can significantly slow the course of AS, suggesting that it could be a viable therapeutic option for AS.
Gao M, etal., J Immunol. 2015 Jul 15;195(2):672-82. doi: 10.4049/jimmunol.1403155. Epub 2015 Jun 5.
Cardiac dysfunction is a major consequence of sepsis/septic shock and contributes to the high mortality of sepsis. Innate and inflammatory responses mediated by TLRs play a critical role in sepsis-induced cardiac dysfunction. MicroRNA-146 (miR-146) was first identified as a negative regulator in inn
ate immune and inflammatory responses induced by LPS. This study examined whether miR-146a will have a protective effect on sepsis-induced cardiac dysfunction. Lentivirus-expressing miR-146a (LmiR-146a) or lentivirus-expressing scrambled miR (LmiR-control) was delivered into the myocardium via the right carotid artery. Seven days after transfection, mice were subjected to cecal ligation and puncture (CLP). Untransfected mice were also subjected to CLP-induced sepsis. Cardiac function was examined by echocardiography before and 6 h after CLP. In vitro studies showed that increased miR-146a levels suppress LPS-induced IκBα phosphorylation and inflammatory cytokine production in both H9C2 cardiomyocytes and J774 macrophages. In vivo transfection of LmiR-146a attenuated sepsis-induced cardiac dysfunction. The values for percent ejection fraction and percent fractional shortening in LmiR-146a-transfected CLP mice were significantly greater than in untransfected CLP control. LmiR-146a transfection prevented sepsis-induced NF-κB activity, suppressed IRAK and TRAF6 expression in the myocardium, and attenuated sepsis-induced inflammatory cytokine production in both plasma and peritoneal fluid. In addition, LmiR-146a transfection decreased sepsis-induced infiltration of neutrophils and macrophages into the myocardium. LmiR-146a can also transfect macrophages in the periphery. We conclude that miR-146a attenuates sepsis-induced cardiac dysfunction by preventing NF-κB activation, inflammatory cell infiltration, and inflammatory cytokine production via targeting of IRAK and TRAF6 in both cardiomyocytes and inflammatory monocytic cells.
OBJECTIVE: Several autoimmune disorders, including systemic sclerosis (SSc), are characterized by a strong sex bias. To date, it is not known whether genes on the sex chromosomes influence SSc susceptibility. Recently, an IRAK1 haplotype that contains the 196Ph
e functional variant (rs1059702), located on Xq28, was found to confer susceptibility to systemic lupus erythematosus (SLE). This study was undertaken to test for an association between SSc and the IRAK1 SLE risk haplotype. METHODS: We tested for an association with the IRAK1 SLE risk haplotype in a discovery set of 849 SSc patients and 625 controls. IRAK1 rs1059702 was further genotyped in a replication set, which included Caucasian women from Italy (493 SSc patients and 509 controls) and Germany (466 SSc patients and 1,083 controls). RESULTS: An association between the IRAK1 haplotype and SSc was detected in the discovery set. In both the discovery and replication sets, the rs1059702 TT genotype was found to be associated with specific SSc subsets, highlighting a potential contribution to disease severity. A meta-analysis provided evidence of an association of both the T allele and TT genotype with the overall disease, with an odds ratio (OR) of 1.20 and 95% confidence interval (95% CI) of 1.06-1.35 for the T allele (P = 0.003) and an OR of 1.49 and 95% CI of 1.06-2.10 for the TT genotype (P = 0.023). However, the most notable associations were observed with the diffuse cutaneous, anti-topoisomerase I antibody positive, and SSc-related fibrosing alveolitis subsets (OR 2.35 [95% CI 1.51-3.66], P = 1.56 x 10(-4), OR 2.84 [95% CI 1.87-4.32], P = 1.07 x 10(-6), and OR 2.09 [95% CI 1.35-3.24], P = 9.05 x 10(-4), respectively). CONCLUSION: Our study provides the first evidence of an association between IRAK1 and SSc, demonstrating that a sex chromosome gene directly influences SSc susceptibility and its phenotypic heterogeneity.
Landais I, etal., PLoS Pathog. 2015 May 8;11(5):e1004881. doi: 10.1371/journal.ppat.1004881. eCollection 2015 May.
Human Cytomegalovirus (HCMV) encodes multiple microRNAs (miRNAs) whose functions are just beginning to be uncovered. Using in silico approaches, we identified the Toll-Like Receptor (TLR) innate immunity pathway as a possible target of HCMV miRNAs. Luciferase reporter assay screens further identifi
ed TLR2 as a target of HCMV miR-UL112-3p. TLR2 plays a major role in innate immune response by detecting both bacterial and viral ligands, including HCMV envelope proteins gB and gH. TLR2 activates a variety of signal transduction routes including the NFkappaB pathway. Furthermore, TLR2 plays an important role in controlling CMV infection both in humans and in mice. Immunoblot analysis of cells transfected with a miR-UL112-3p mimic revealed that endogenous TLR2 is down-regulated by miR-UL112-3p with similar efficiency as a TLR2-targeting siRNA (siTLR2). We next found that TLR2 protein level decreases at late times during HCMV infection and correlates with miR-UL112-3p accumulation in fibroblasts and monocytic THP1 cells. Confirming direct miR-UL112-3p targeting, down-regulation of endogenous TLR2 was not observed in cells infected with HCMV mutants deficient in miR-UL112-3p expression, but transfection of miR-UL112-3p in these cells restored TLR2 down-regulation. Using a NFkappaB reporter cell line, we found that miR-UL112-3p transfection significantly inhibited NFkappaB-dependent luciferase activity with similar efficiency as siTLR2. Consistent with this observation, miR-UL112-3p transfection significantly reduced the expression of multiple cytokines (IL-1beta, IL-6 and IL-8) upon stimulation with a TLR2 agonist. Finally, miR-UL112-3p transfection significantly inhibited the TLR2-induced post-translational activation of IRAK1, a kinase located in the upstream section of the TLR2/NFkappaB signaling axis. To our knowledge, this is the first identified mechanism of TLR2 modulation by HCMV and is the first report of functional targeting of TLR2 by a viral miRNA. These results provide a novel mechanism through which a HCMV miRNA regulates the innate immune response by down-regulating TLR-2 expression.
Heiseke AF, etal., J Immunol. 2015 Dec 15;195(12):5787-94. doi: 10.4049/jimmunol.1501874. Epub 2015 Nov 11.
IL-1R-associated kinase (IRAK) 1 is an important component of the IL-1R and TLR signaling pathways, which influence Th cell differentiation. In this study, we show that IRAK1 promotes Th17 development by mediating IL-1beta-induced upregulation of IL-23R and subs
equent STAT3 phosphorylation, thus enabling sustained IL-17 production. Moreover, we show that IRAK1 signaling fosters Th1 differentiation by mediating T-bet induction and counteracts regulatory T cell generation. Cotransfer experiments revealed that Irak1-deficient CD4(+) T cells have a cell-intrinsic defect in generating Th1 and Th17 cells under inflammatory conditions in spleen, mesenteric lymph nodes, and colon tissue. Furthermore, IRAK1 expression in T cells was shown to be essential for T cell accumulation in the inflamed intestine and mesenteric lymph nodes. Transcriptome analysis ex vivo revealed that IRAK1 promotes T cell activation and induction of gut-homing molecules in a cell-intrinsic manner. Accordingly, Irak1-deficient T cells failed to upregulate surface expression of alpha4beta7 integrin after transfer into Rag1(-/-) mice, and their ability to induce colitis was greatly impaired. Lack of IRAK1 in recipient mice provided additional protection from colitis. Therefore, IRAK1 plays an important role in intestinal inflammation by mediating T cell activation, differentiation, and accumulation in the gut. Thus, IRAK1 is a promising novel target for therapy of inflammatory bowel diseases.
Adams AK, etal., Oncotarget. 2015 Dec 22;6(41):43395-407. doi: 10.18632/oncotarget.6028.
The chromatin-binding DEK protein was recently reported to promote the growth of HPV+ and HPV- head and neck squamous cell carcinomas (HNSCCs). Relevant cellular and molecular mechanism(s) controlled by DEK in HNSCC remain poorly understood. While DEK is known to regulate specific transcriptional
targets, global DEK-dependent gene networks in HNSCC are unknown. To identify DEK transcriptional signatures we performed RNA-Sequencing (RNA-Seq) in HNSCC cell lines that were either proficient or deficient for DEK. Bioinformatic analyses and subsequent validation revealed that IRAK1, a regulator of inflammatory signaling, and IRAK1-dependent regulatory networks were significantly repressed upon DEK knockdown in HNSCC. According to TCGA data, 14% of HNSCC specimens overexpressed IRAK1, thus supporting possible oncogenic functions. Furthermore, genetic or pharmacologic inhibition of IRAK1 in HNSCC cell lines was sufficient to attenuate downstream signaling such as ERK1/2 and to induce HNSCC cell death by apoptosis. Finally, targeting DEK and IRAK1 simultaneously enhanced cell death as compared to targeting either alone. Our findings reveal that IRAK1 promotes cell survival and is an attractive therapeutic target in HNSCC cells. Thus, we propose a model wherein IRAK1 stimulates tumor signaling and phenotypes both independently and in conjunction with DEK.
Wang H, etal., IUBMB Life. 2018 Jun;70(6):479-490. doi: 10.1002/iub.1747. Epub 2018 Apr 29.
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 us
Hung PS, etal., PLoS One. 2013 Nov 26;8(11):e79926. doi: 10.1371/journal.pone.0079926.
MicroRNAs are short non-coding RNAs that regulate gene expression and are crucial to tumorigenesis. Oral squamous cell carcinoma (OSCC) is a prevalent malignancy worldwide. Up-regulation of miR-146 has been identified in OSCC tissues. However, the roles of miR-146 in carcinogenesis are controversial
as it is suppressive in many other malignancies. The present study investigated the pathogenic implications of miR-146a in oral carcinogenesis. Microdissected OSCC exhibits higher levels of miR-146a expression than matched adjacent mucosal cells. The plasma miR-146a levels of patients are significantly higher than those of control subjects; these levels decrease drastically after tumor resection. miR-146a levels in tumors and in patients' plasma can be used to classify OSCC and non-disease status (sensitivity: >0.72). Exogenous miR-146a expression is significantly increased in vitro oncogenic phenotypes as well as during xenograft tumorigenesis and OSCC metastasis. The plasma miR-146a levels of these mice parallel the xenograft tumor burdens of the mice. A miR-146a blocker abrogates the growth of xenograft tumors. miR-146a oncogenic activity is associated with down-regulation of IRAK1, TRAF6 and NUMB expression. Furthermore, miR-146a directly targets the 3'UTR of NUMB and a region within the NUMB coding sequence when suppressing NUMB expression. Exogenous NUMB expression attenuates OSCC oncogenicity. Double knockdown of IRAK1 and TRAF6, and of TRAF6 and NUMB, enhance the oncogenic phenotypes of OSCC cells. Oncogenic enhancement modulated by miR-146a expression is attenuated by exogenous IRAK1 or NUMB expression. This study shows that miR-146a expression contributes to oral carcinogenesis by targeting the IRAK1, TRAF6 and NUMB genes.
Yang G and Zhao Y, Yonsei Med J. 2020 Aug;61(8):660-669. doi: 10.3349/ymj.2020.61.8.660.
PURPOSE: Neonatal hypoxic ischemic encephalopathy (HIE) is an essential factor underlying neonatal death and disability. This study sought to explore the role of miR-146b-5p in regulating neonatal HIE. MATERIALS AND METHODS: In vitro and in vivo HIE models were established in PC
12 cells and 10-day neonatal Sprague Dawley rats, respectively. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to assess miR-146b-5p expression and inflammatory factors [interleukin (IL)-6 and tumor necrosis factor (TNF)-α] in brain lesions and PC12 cells, while enzyme-linked immunosorbent assay was employed to detect the expression of oxidative stress factors (SOD and GSH-Px). Gain- and loss-assays of miR-146b-5p were conducted to verify its role in modulating the viability and apoptosis of PC12 cells under oxygen-glucose deprivation (OGD) treatment. Expression of TLR4, IRAK1, TRAF6, TAK1, and NF-κB were examined by qRT-PCR and/or Western blot. Dual luciferase activity assay was conducted to identify relationships between miR-146b-5p and IRAK1. RESULTS: In the HIE models, significant oxidative stress and inflammatory responses emerged upon upregulation of TLR4/IRAK1/TRAF6/TAK1/NF-κB signaling. Overexpression of miR-146b-5p greatly inhibited OGD-induced PC12 cell injury, inflammatory responses, and oxidative stress. Inhibiting miR-146b-5p, however, had the opposite effects. IRAK1 was found to be a target of miR-146b-5p, and miR-146b-5p overexpression suppressed the activation of IRAK1/TRAF6/TAK1/NF-κB signaling. CONCLUSION: This study demonstrated that miR-146b-5p overexpression alleviates HIE-induced neuron injury by inhibiting the IRAK1/TRAF6/TAK1/NF-κB pathway.
Song GG, etal., Z Rheumatol. 2015 Sep;74(7):637-45. doi: 10.1007/s00393-014-1493-x.
OBJECTIVE: The aim of this study was to explore whether polymorphisms in miR-146a, miR-499 and IRAK1 are associated with susceptibility to inflammatory arthritis. METHODS: Manual searches performed in the MEDLINE and EMBASE databases were used to identify publis
hed articles in which the roles of microRNA (miRNA) and IRAK1 polymorphisms in inflammatory arthritis were determined. A meta-analysis was conducted to investigate associations of the miR-146a rs2910164, miR-499 rs3746444, IRAK1 rs3027898 and IRAK1 rs1059703 polymorphisms with susceptibility to inflammatory arthritis. RESULTS: Nine studies containing 1224 patients and 1841 controls were included in the meta-analysis. The meta-analysis revealed no association between inflammatory arthritis and the rs2910164 C allele of miR-146a (odds ratio, OR = 0.974; 95 % confidence interval, CI = 0.810-1.091; p = 0.650). Stratification by ethnicity or disease type revealed no association between the miR-146a C allele and inflammatory arthritis in European, Middle Eastern or Asian patients with rheumatoid arthritis (RA) or juvenile idiopathic arthritis (JIA). However, the meta-analysis revealed an overall association between RA and the miR-499 rs374644 C (OR = 1.123, 95 % CI = 1.019-2.586, p = 0.041); stratification by ethnicity revealed a particular association in Middle Eastern populations (OR = 1.943, 95 % CI = 1.508-2.504, p = 2.7 x 10(-8)). The meta-analysis of IRAK1 polymorphisms revealed an association between inflammatory arthritis and the rs3027898 CC genotype (OR = 2.602, 95 % CI = 1.387-4.879, p = 0.003). An analysis using the homozygote contrast showed the same pattern for the rs3027898 CC genotype (OR = 2.472, 95 % CI = 1.300-4.700, p = 0.006). No association between inflammatory arthritis and the rs1059703 polymorphism was found. CONCLUSION: This meta-analysis suggests that the miR-499 rs374644 and IRAKI rs3027898 polymorphisms are associated with susceptibility to inflammatory arthritis.
Chatzikyriakidou A, etal., Scand J Immunol. 2010 May;71(5):382-5. doi: 10.1111/j.1365-3083.2010.02381.x.
MicroRNAs have shown different expression patterns in immune diseases. The present study explores the association of miRNA-146a variant rs2910164 and of two IRAK1 (target of miR-146a) polymorphisms rs3027898 and rs1059703 with psoriasic arthritis (PsA). Twenty-n
ine PsA and 66 controls were enrolled in the study. To study if the statistical significant differences between patients with PsA and controls are independent to psoriasis, we expanded the study in 49 patients with ankylosing spondylitis (AS). Strong statistical significant difference was observed in IRAK1 rs3027898 polymorphism distribution between patients with PsA and controls (P = 0.003), as between patients with AS and controls (P < 0.001). Marginally significant difference was observed in distribution of IRAK1 rs1059703 genotypes between patients with PsA and controls (P = 0.058), but no difference was observed in miRNA-146a rs2910164 distribution (P = 0.394). This is the first study that addresses IRAK1 rs3027898 polymorphism association with PsA susceptibility, but further studies could help to understand the extent of the proposed association.
Abdel Motaleb FI, etal., Virus Res. 2017 Jun 15;238:24-28. doi: 10.1016/j.virusres.2017.05.026. Epub 2017 Jun 3.
BACKGROUND: Hepatitis C virus (HCV) is a life threatening human pathogen. It has been found that miRNA146a regulates innate immunity, inflammatory response and antiviral pathway. We evaluated miRNA146a expression by real-time PCR and IL-1 receptor associated kinase 1 (IRAK1
ight:700;'>IRAK1) and TNF receptor-associated factor 6 (TRAF6) levels by ELISA in serum of 36 HCV viremia patients and 42 age and gender matched healthy controls. RESULTS: miRNA146a expression was significantly higher in HCV patients with a best cut off value 1.63 to discriminate between HCV patients and healthy controls. Meanwhile, it was negatively correlated to IRAK1 and TRAF6 levels and positively correlated to viral load in HCV patients. CONCLUSIONS: miRNA146a has a potential role in HCV infection and viral replication through IRAK1 and TRAF6. It can also serve as a new screening method for HCV.
