Interleukin-1 Receptor-associated Kinase 4 Gene Research Articles

Unraveling Extremely Damaging IRAK4 Variants and Their Potential Implications for IRAK4 Inhibitor Efficacy.

Interleukin-1-receptor-associated kinase 4 (IRAK4) possesses a crucial function in the toll-like receptor (TLR) signaling pathway, and the dysfunction of this molecule could lead to various infectious and immune-related diseases in addition to cancers. IRAK4 genetic variants have been linked to various types of diseases. Therefore, we conducted a comprehensive analysis to recognize the missense variants with the most damaging impacts on IRAK4 with the employment of diverse bioinformatics tools to study single-nucleotide polymorphisms' effects on function, stability, secondary structures, and 3D structure. The residues' location on the protein domain and their conservation status were investigated as well. Moreover, docking tools along with structural biology were engaged in analyzing the SNPs' effects on one of the developed IRAK4 inhibitors. By analyzing IRAK4 gene SNPs, the analysis distinguished ten variants as the most detrimental missense variants. All variants were situated in highly conserved positions on an important protein domain. L318S and L318F mutations were linked to changes in IRAK4 secondary structures. Eight SNPs were revealed to have a decreasing effect on the stability of IRAK4 via both I-Mutant 2.0 and Mu-Pro tools, while Mu-Pro tool identified a decreasing effect for the G198E SNP. In addition, detrimental effects on the 3D structure of IRAK4 were also discovered for the selected variants. Molecular modeling studies highlighted the detrimental impact of these identified SNP mutant residues on the druggability of the IRAK4 ATP-binding site towards the known target inhibitor, HG-12-6, as compared to the native protein. The loss of important ligand residue-wise contacts, altered protein global flexibility, increased steric clashes, and even electronic penalties at the ligand-binding site interfaces were all suggested to be associated with SNP models for hampering the HG-12-6 affinity towards IRAK4 target protein. This given model lays the foundation for the better prediction of various disorders relevant to IRAK4 malfunction and sheds light on the impact of deleterious IRAK4 variants on IRAK4 inhibitor efficacy.

Associations of IRAK1 Gene Polymorphisms and mRNA Expression With NMOSD Risk in the Northern Chinese Han Population.

Objectives: Interleukin (IL)-1 receptor-associated kinase 1 (IRAK1) is a very important immunomodulatory gene for autoimmune diseases located on the X chromosome. However, there was little study about the correlation of IRAK1 functional single nucleotide polymorphisms with mRNA expression in neuromyelitis optica spectrum disorder (NMOSD) patients. In this study, we aimed to investigate the plausible association of IRAK1 polymorphism, IRAK1 mRNA expression, and NMOSD risk in the northern Chinese Han population.Methods: Four loci of IRAK1 gene (rs1059702, rs7061789, rs1059703, and rs3027898) were genotyped using multiplex SNaPshot technique in 102 NMOSD patients and 213 healthy subjects. Allele, genotype, and haplotype frequencies were compared. Stratified analyses were conducted by age, sex, AQP4 status, and age of onset. IRAK1 mRNA levels in the peripheral blood mononuclear cells of 30 NMOSD patients (of active phase) and 15 healthy control subjects were detected using qPCR. The correlations between the SNP polymorphisms and mRNA expression levels of genes were tested using non-parametric tests.Results: The minor allele frequencies (MAF) of these four locis were significantly lower in NMOSD cases than that of the controls. The frequencies of rs1059703G/G genotype, rs1059702A/A genotype, rs3027898 C/C genotype, and rs7061789G/G genotype were higher in the case group than that of the control group. Haplotype analysis revealed that the major haplotype “G-A-C-G” (alleles in the order of SNPs rs1059703, rs1059702, rs3027898, and rs7061789), containing the risk alleles, conferred an adverse effect on NMOSD. The level of IRAK1mRNA was markedly higher in NMOSD when compared to the healthy control groups. The IRAK1mRNA levels of female patients with the major haplotype were significantly higher compared to those with other haplotypes and to the male patients with the same genotype.Conclusion: IRAK1 polymorphisms were highly correlated with NMOSD susceptibility. Its haplotype G-A-C-G (rs1059703-rs1059702-rs3027898-rs7061789) confers increasing the risk of NMOSD in female patients. The IRAK1 risk haplotype G-A-C-G upregulated IRAK1 mRNA expression in female NMOSD patients. Our study provides a novel insight into the molecular mechanism of the pathogenesis of NMOSD and reveals that IRAK1 is the potential mechanism-specific druggable target in NMOSD disease.

Variations of interleukin-1 receptor-associated kinase-4 encoding gene were not associated with post-bronchiolitis lung function.

Interleukin-1 receptor associated kinase-4 (IRAK4) encoded by the IRAK4 gene mediates signals of innate immunity. Single nucleotide polymorphisms (SNP) of the IRAK4 rs4251513 and rs4251520 were associated with an increased risk of early transient wheezing, when 94 SNPs were studied in 2007 Dutch and 7242 French children prospectively followed-up for eight years from birth (1).

MiR-146a Enhances the Sensitivity of Breast Cancer Cells to Paclitaxel by Downregulating IRAK1.

Objective: To investigate the effect of miR-146a on the sensitivity of breast cancer cells to paclitaxel (PTX). Materials and Methods: The mRNA expressions of miR-146a in normal breast cancer cells, MCF-7, and PTX-resistant breast cancer cells, MCF-7/PTX, were detected by reverse transcriptase-polymerase chain reaction (RT-PCR). MTS was used to analyze the cytotoxicity treated with different concentrations of PTX. Overexpressed and silenced cell lines of miR-146a and interleukin-1 receptor-associated kinase 1 (IRAK1) were constructed, respectively. Cells were treated with PTX and observed the changes of cell morphology. Proliferation was detected by clone formation assay. Invasion and migration were measured by transwell. RT-PCR was applied to detect the expression of IRAK1 gene. Dual luciferase report was performed to validate the target relationship between miR-146a and IRAK1. Salvage experiments were used to further verify the relationship between miR-146a and IRAK1. Results: PTX reduces the viability of MCF-7 and MCF-7/PTX cells in a dose-dependent manner. The IC50 of PTX in MCF-7 cells was significantly lower compared with MCF-7/PTX cells (p < 0.05). Compared with MCF-7/PTX cells, the expression of miR-146a gene in MCF-7 cells was significantly increased, while the expression of IRAK1 gene was significantly reduced (p < 0.05). Cell proliferation, invasion, and migration were decreased after miR-146a overexpression or IRAK1 silencing. Whereas, miR-146a silencing and IRAK1 overexpression can increase cell proliferation, invasion, and migration ability. Salvage experiments further verify that IRAK1 can weaken the role of miR-146a. Conclusion: miR-146a can enhance the sensitivity of breast cancer cells to PTX; the mechanism may be related to the downregulation of IRAK1.

Interleukin-1 receptor-associated kinase-4 gene variation may increase post-bronchiolitis asthma risk.

Evidence based on studies of the encoding genes suggests that interleukin-1 receptor-associated kinase-4 (IRAK4) plays a role in childhood asthma and allergy. Our aim was to evaluate the associations of six IRAK4 gene polymorphisms with presence of asthma and allergic rhinitis and use of inhaled corticosteroids (ICSs) for asthma at 5-7 and 11-13years of ages after hospitalisation for bronchiolitis at younger than 6months of age. IRAK4 rs4251513, rs4251520, rs4251522, rs4251578, rs79154645 and rs13852554 polymorphisms were determined in 141 former bronchiolitis patients prospectively followed up until 5-7 and in 125 children until 11-13years of age. The homozygous variant IRAK4 rs4251513 genotype was associated with the presence of asthma and allergic rhinitis and use of ICSs at 5-7 and 11-13years of ages in univariate analyses. Statistical significance remained for the presence of asthma and use of ICSs but was lost in the case of allergic rhinitis in multivariate analyses. The adjusted odds ratios were 3.48 and 4.16 for asthma and 5.22 and 14.00 for ICS use at these two ages. The homozygous variant IRAK4 rs4251513 genotype was constantly associated with post-bronchiolitis asthma and asthma medication in school-aged children.

Correlations of miR-146a and IRAK1 gene polymorphisms with ankylosing spondylitis.

The aim of this study was to explore the correlations of micro ribonucleic acid (miR)-146a and interleukin 1 receptor associated kinase 1 (IRAK1) gene polymorphisms with ankylosing spondylitis. A total of 200 patients with ankylosing spondylitis in our hospital were enrolled in the disease group. The diagnosis of ankylosing spondylitis was in accordance with the 1984 New York Revised Criteria for Ankylosing Spondylitis. Meanwhile, 200 healthy people were taken as the control group. Peripheral blood was collected from patients in both disease group and control group. Subsequently, polymorphic regions of rs2910164 and rs7702165 in miR-146a and those of rs763737 and rs3027898 in IRAK1 were amplified by polymerase chain reaction (PCR). The polymorphisms were analyzed by sequencing based on gene expression and clinical data of patients. The allele distribution of miR-146a rs7702165 (p=0.008) and that of IRAK1 rs3027898 (p=0.004) in disease group were significantly different from those in control group. Besides, the allele T frequency of miR-146a rs7702165 and the allele A frequency of IRAK1 rs3027898 were relatively higher in disease group. Statistically significant differences in the genotype distribution of miR-146a rs2910164 (p=0.032) and rs7702165 (p=0.000) and that of IRAK1 rs3027898 (p=0.001) were observed between disease group and control group. In addition, the frequencies of genotypes CG and TT of miR-146a rs7702165 and the frequency of genotype AA of IRAK1 rs3027898 were higher in disease group. Moreover, the distribution in the dominant model of IRAK1 rs3027898 (p=0.011) and that in the recessive model of miR-146a rs7702165 (p=0.015) showed remarkable differences between disease group and control group. The frequency of CC+CA in the dominant model of IRAK1 rs3027898 and that of TG+GG in the recessive model of miR-146a rs7702165 in disease group were lower than those in control group. Additionally, the haplotype CG distribution of miR-146a rs2910164 and rs7702165 (p<0.043) and the haplotype GA distribution of IRAK1 rs763737 and rs3027898 (p=0.035) in disease group displayed significant differences compared with those in control group. It was discovered that the genotype of miR-146a rs2910164 was correlated with the expressions of miR-146a (p=0.024) and IRAK1 (p=0.002). Similarly, IRAK1 gene polymorphism rs763737 was related to the expression of IRAK1 (p=0.023), Furthermore, miR-146a gene polymorphism rs7702165 was associated with the level of human leukocyte antigen B27 (HLA-B27) (p<0.05), and patients with genotype GG exhibited a lower level of HLA-B27. In addition, it was found that IRAK1 gene polymorphism rs3027898 was correlated with the C-reactive protein (CRP) level of patients (p<0.05), and CRP level was relatively high in patients with genotype CC. MiR-146a and IRAK1 gene polymorphisms are prominently associated with ankylosing spondylitis.

Cellular microRNA, miR-1343-5p, modulates IFN-I responses to facilitate feline panleukopenia virus replication by directly targeting IRAK1 gene

Feline panleukopenia is an acute, highly contagious, and fatal infectious disease caused by feline panleukopenia virus (FPV) and has led to severe consequences on pets, economically important animals, and the wildlife industry. MicroRNAs (miRNAs) play significant roles in the host-pathogen interaction by modulating cellular factors expression which are essential for viral replication or host innate immune response to infection. However, the role of host miRNA response in FPV infection remains to be discovered. In this study, we screened nine host miRNAs associated with FPV infection that were previously implicated in innate immunity or antiviral functions. We found that miR-1343-5p overexpression strongly promoted FPV-BJ04 genomic DNA. Subsequently, the expression of host miR-1343-5p was upregulated by FPV-BJ04 infection in vitro and in vivo. In addition, we demonstrated that miR-1343-5p was a negative regulator of the IFN-I signaling pathway, thereby promoting FPV infection. Bioinformatic analysis combined with molecular biological assay indicated that interleukin-1 receptor-associated kinase 1 (IRAK1) is a putative target of miR-1343-5p. Collectively, our findings emphasize the importance of miR-1343-5p in host defense against FPV, thus, enhancing our understanding of its pathogenic mechanism.

Identification and expression analysis of IRAK-4 cDNA and its gene from the ayu Plecoglossus altivelis altivelis

Interleukin-1 receptor-associated kinase 4 (IRAK-4) is an important component of the mammalian innate and adaptive defense system against infectious disease. In this study, ayu Plecoglossus altivelis altivelis IRAK-4 cDNA and genomic DNA were cloned and analyzed. The open reading frame of ayu IRAK-4 cDNA encodes 463 amino acids, including a death domain and a serine/threonine protein kinase domain of the mammalian IRAK-4 motif. The ayu IRAK-4 gene comprises 11 exons, and was found to be very similar to vertebrate IRAK-4 genes described thus far. Ayu IRAK-4 mRNA was expressed in all tissues, and predominantly in the gill, heart, intestine, whole kidney, and spleen. At 12 h after immersion challenge with Flavobacterium psychrophilum, ayu IRAK-4 mRNA expression in the whole blood was up-regulated (21.6-fold) compared to the control. The present study suggests that ayu IRAK-4 may be involved in the immune response.

IRAK4 gene polymorphism and odontogenic maxillary sinusitis.

ObjectivesThis study aimed to evaluate whether a specific interleukin-1 receptor-associated kinase-4 (IRAK4) gene polymorphism had any influence on the development of changes in maxillary sinus, particularly in the presence of etiological factors of dental origin.Materials and methodsThe study population included 153 Portuguese Caucasians that were selected from a database of 504 retrospectively analysed computed tomography (CT) scans. A genetic test was performed, and a model was created through logistic analysis and regression coefficients. The statistical methodologies included were the independent Chi test, Fisher’s exact test, binary logistic regression and the receiver operating characteristic (ROC) curve.ResultsThe estimated prevalence of IRAK4 gene polymorphism found in a Portuguese Caucasian population was 26.8 % (CI 95 %) [20.1, 34.7 %]. A model to predict the inflammatory response in the maxillary sinus in the presence etiological factors of dental origin was constructed. This model had the following as variables: previously diagnosed sinusitis, sinus pressure symptoms, cortical bone loss observed on CT, positive genetic test result and radiographic examination that revealed the roots of the teeth communication with the maxillary sinus, which are interpreted as risk factors.ConclusionsThe constructed model should be considered an initial clinical tool. The area under the ROC curve found, AUC = 0.91, revealed that the model correctly predicts the outcome in 91.1 % of cases.Clinical relevanceThe clinical relevance of this study lies in trying to achieve a potential tool (a model) that may assist the clinician in the implementation of suitable dental treatment plans in complex cases, with probable involvement of the maxillary sinus.

Effects of IL-1 Receptor-Associated Kinase-4 Gene Silencing on Human Osteoblast-Like Cells

The aim of this study is to identify the effects of interleukin-1 receptor-associated kinase-4 (IRAK-4) gene silencing on human osteoblast-like cells. The siRNA sequences of the target gene, IRAK-4, were constructed and transferred into MG63 cells (control group = MG63 cells; SC group = MG63 cells transfected with scrambled IRAK-4 siRNA; KD group = MG63 cells transfected with 75 nM IRAK-4 siRNA). The morphological changes, cell growth, cell-cycle progression, apoptosis, and the expression of various cytokines and proteins were compared. Compared with the control and SC groups, IRAK-4 gene silencing in MG63 cells caused morphological changes, inhibited growth, altered the cell-cycle distribution, increased apoptosis (p < 0.05), decreased bone alkaline phosphatase and osteocalcin levels (p < 0.05), and decreased protein expression of Bcl-2/Bax and Bcl-2, p-JNK1/2, p-ERK1/2, and p-p38MAPK (p < 0.05). The results indicated that IRAK-4 gene silencing in MG63 cells inhibited cell proliferation and function and increase apoptosis, which may be related to the decreased Bcl-2/Bax ratio and inhibition of the protein expression of various components of the mitogen-activated protein kinase pathways. The results of this study may help improve the understanding of the relationship between IRAK-4 and osteoblast-like cells and the interactions between various cytokines in the periprosthetic inflammatory environment.

Association between single-nucleotide polymorphisms in the IRAK-4 gene and allergic rhinitis

To investigate the genetic association pattern between single-nucleotide polymorphisms (SNP) in the interleukin-1 receptor-associated kinase 4 (IRAK-4) gene and allergic rhinitis (AR). A population of 379 patients with the diagnosis of AR and 333 healthy controls who lived in Beijing region was recruited. A total of 8 reprehensive marker SNP which were in IRAK-4 gene region were selected according to the Beijing people database from Hapmap website. The individual genotyping was performed by MassARRAY platform. SPSS 13.0 software was used for statistic analysis. Subgroup analysis for the presence of different allergen sensitivities displayed associations only in the house dust mite-allergic cohorts (rs3794262: P = 0.0034, OR = 1.7388; rs4251481: P = 0.0023, OR = 2.6593), but not in subjects who were allergic to pollens as well as mix allergens. The potential genetic contribution of the IRAK-4 gene to AR demonstrated an allergen-dependant association pattern in Chinese population.

Reduced oxidative tissue damage during endotoxemia in IRAK-1 deficient mice

The generation of reactive oxygen species (ROS) triggered by bacterial endotoxin lipopolysaccharide (LPS) plays a key role during the pathogenesis of sepsis. Given the key role that the interleukin-1 receptor associated kinase-1 (IRAK-1) plays in LPS-mediated Toll-like-receptor 4 (TLR4) pathway, we herein tested whether deletion of IRAK-1 gene in mice may render protection from LPS-induced oxidative tissue damage. In this report, we studied the levels of oxidative stress in vital organs including liver, kidney, and brain from wild type (WT) and IRAK-1 deficient mice injected with a lethal dose of LPS (25mg/kg), a TLR4-specific agonist. We demonstrated that LPS challenge induced marked elevation of lipid peroxidation and nitrite levels in the plasma and tissues of WT mice, as well as elevated pro-inflammatory mediators. In contrast, IRAK-1 deficient mice had significantly lower lipid peroxidation and nitrite levels, as well as lower levels of pro-inflammatory mediators. Mechanistically, LPS triggered higher levels of iNOS activity and elevated membrane translocation of p47phox, a key component of NADPH oxidase in immune cell derived from WT mice compared to IRAK-1 deficient mice. Additionally, tissues harvested from WT mice injected with LPS exhibited reduced activities of anti-oxidant enzymes including glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD). In contrast, LPS challenge failed to reduce the activities of GPx and SOD in IRAK-1 deficient tissues. As a consequence, LPS caused significantly pronounced damage to liver and kidney tissues in WT mice as compared to IRAK-1 deficient mice.

Association pattern of interleukin-1 receptor-associated kinase-4 gene polymorphisms with allergic rhinitis in a Han Chinese population.

ObjectiveInterleukin-1 receptor-associated kinase-4 (IRAK-4) encodes a kinase that is essential for NF-kB activation in Toll-like receptor and T-cell receptor signaling pathways, indicating a possible crosstalk between innate and acquired immunities. We attempted to determine whether the polymorphisms in the Interleukin-1 receptor-associated kinase-4 (IRAK-4) gene are associated with allergic rhinitis (AR) in the Han Chinese population.MethodsA population of 379 patients with AR and 333 healthy controls was studied. Blood was drawn for DNA extraction and total serum immunoglobulin E (IgE). A total of 11 single nucleotide polymorphisms (SNPs) in IRAK-4 were selected and individually genotyped.ResultsSignificant allelic differences between cases and controls were obtained for the SNP of rs3794262 in the IRAK-4 gene. In the stratified analysis for gender, two SNPs (rs4251431 and rs6582484) in males appeared as significant associations. Subgroup analysis for the presence of different allergen sensitivities displayed associations only in the house dust mite-allergic cohorts (rs3794262, rs4251481). None of the selected SNPs in IRAK-4 was associated with total IgE level. The haplotype analyisis indicated GCCTGCGA was significantly associated with AR. The SNP-SNP interaction information analysis indicated that the selected sets of polymorphisms had no synergistic effect.ConclusionsOur findings did not support the potential contribution of the IRAK-4 gene to serum IgE levels. However, the results demonstrated a gender- and allergen-dependant association pattern between polymorphisms in IRAK-4 and AR in Chinese population.

Annotation of novel transcripts putatively relevant for bovine fat metabolism

Two bovine transcripts encoded by the interleukin-1 receptor-associated kinase 1 (IRAK1) gene and the locus LOC618944 predicted as similar to human chromosome 6 open reading frame 52 (C6orf52) gene had indicated divergent expression in bovine skeletal muscle containing different amount of intramuscular fat in a pilot screening experiment. However, for both loci any role in the regulation of energy or fat metabolism is not yet described. In this study, we validated and refined gene structure, screened for mRNA splice variants and analyzed the tissue-specific gene expression patterns of both loci as a prerequisite to elucidate their potential physiological function. Based on comparative sequence analysis, a new full-length gene model for the bovine IRAK1 gene was developed and confirmed experimentally. Expression of IRAK1 mRNA was found in a variety of tissues, and a splice variant was identified in skeletal muscle caused by an in-frame deleted segment of 210 bp affecting regions of intrinsic disorder in the respective protein. For the locus LOC618944, our data contributed to a revised gene model and its assignment to BTA23 (bovine chromosome 23) on the current bovine genome assembly supported by comparative similarity analysis between the bovine and human genomes and experimental data. Furthermore, we identified several splice variants in mammary gland, fat and skeletal muscle tissue and detected a highly similar processed pseudogene on BTA26. All transcript variants of LOC618944 detected in the analyzed tissues represent noncoding RNAs. For both loci, our results suggest yet undetected physiological functions in tissues relevant for fat or energy metabolism in cattle.

The association between innate immunity gene ( IRAK1) and C-reactive protein in the Diabetes Heart Study

Evidence suggests that interleukin-1 receptor-associated kinase-1 (IRAK1), fundamental in the toll-like receptor pathway (TLR), may play a more specific role in atherosclerosis. Methods: Caucasian women ( N = 529) and men ( N = 467) from the Diabetes Heart Study (DHS) were genotyped at four loci within the IRAK1 gene located on the X chromosome. Generalized estimating equations (GEE1) were used to evaluate association with C-reactive protein (CRP) for both single SNP and haplotype analyses. Results: For each SNP genotyped, Caucasian women carrying one or two copies of the variant allele had greater CRP concentrations than those carrying the common genotype in both crude and adjusted models. There were 2 major haplotypes, CTTT (82%) and its complement TCCG (13%). The presence of the TCCG haplotype was associated with greater CRP concentrations in Caucasian women ( p = 0.0004) and this relationship was maintained after adjustment for age, BMI, smoking, diabetes, and cholesterol-lowering therapy ( p = 0.003). There was no association between CRP and IRAK1 SNPs in Caucasian men. Conclusion: Variation in the IRAK1 gene is associated with CRP concentration in Caucasian women in DHS. Further studies are needed to reproduce the current finding and to understand the biological relationship between IRAK1 and inflammation related to atherosclerosis.

Effects of IRAK-4-shRNA perfused through portal vein in vivo or in vitro on ischemia/reperfusion injury of liver graft in rats

目的 通过观察活体或冷保存期离体门静脉灌注供肝转染白细胞介素-1受体相关激酶-4(IRAK-4)特异短发夹RNA(shRNA)对再灌注后受体TNF-α产生的影响,判断以IRAK-4为肝移植缺血再灌注损害(I/RI)治疗靶点的可行性并探索可行的shRNA治疗途径.方法雄性SD大鼠,随机分为冷缺血转染组、活体转染组、对照组,以两袖套法建立同种异体肝移植模型.冷缺血转染组于冷缺血期经门静脉灌注转染携带染IRAK-4-shRNA的转染质粒pSIIRAK-4;活体转染组在门静脉袖套吻合完成后,经门静脉分支注入pSIIRAK-4;对照组不予任何处理.按门静脉血流恢复后第0 min、60 min及180 min分为三个亚组,逆转录-聚合酶链式反应及蛋白免疫印记法测定肝组织的染IRAK-4 mRNA和蛋白表达水平;酶连免疫吸附法检测肝组织NF-κB活性及血清TNF-α含量.结果再灌注后活体转染组、对照组的IRAK-4蛋白与mRNA表达水平、NF-κB活性以及TNF-α含量均高于冷缺血转染组(P＜0.01);冷缺血转染组的IRAK-4表达明显抑制,再灌注后各时点差异无显著性(P＞0.05).结论以IRAK-4为靶点的冷缺血shRNAs转染途径能有效减轻肝移植时的I/RI,但能否以IRAK-4作为预防其他器官的I/RI的治疗靶点尚需深入研究。

A Novel Splice Variant of Interleukin-1 Receptor (IL-1R)-Associated Kinase 1 Plays a Negative Regulatory Role in Toll/IL-1R-Induced Inflammatory Signaling

The interleukin-1 (IL-1) receptor-associated kinase 1 (IRAK1) is a member of the IRAK kinase family that plays a pivotal role in the Toll/IL-1 receptor (TIR) family signaling cascade. We have identified a novel splice variant, IRAK1c, which lacks a region encoded by exon 11 of the IRAK1 gene. IRAK1c expression was confirmed by both RNA and protein detection. Although both IRAK1 and IRAK1c are expressed in most tissues tested, IRAK1c is the predominant form of IRAK1 expressed in the brain. Unlike IRAK1, IRAK1c lacks kinase activity and cannot be phosphorylated by IRAK4. However, IRAK1c retains the ability to strongly interact with IRAK2, MyD88, Tollip, and TRAF6. Overexpression of IRAK1c suppressed NF-kappaB activation and blocked IL-1beta-induced IL-6 as well as lipopolysaccharide- and CpG-induced tumor necrosis factor alpha production in multiple cellular systems. Mechanistically, we provide evidence that IRAK1c functions as a dominant negative by failing to be phosphorylated by IRAK4, thus remaining associated with Tollip and blocking NF-kappaB activation. The presence of a regulated, alternative splice variant of IRAK1 that functions as a kinase-dead, dominant-negative protein adds further complexity to the variety of mechanisms that regulate TIR signaling and the subsequent inflammatory response.