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ABSTRACT: Reactive force field (ReaxFF), a recent and novel bond order potential, allows for reactive molecular dynamics (ReaxFF MD) simulations for modeling larger and more complex molecular systems involving chemical reactions when compared with computation intensive quantum mechanical methods. However, ReaxFF MD can be approximately 10-50 times slower than classical MD due to its explicit modeling of bond forming and breaking, the dynamic charge equilibration at each time-step, and its one order smaller time-step than the classical MD, all of which pose significant computational challenges in simulation capability to reach spatio-temporal scales of nanometers and nanoseconds. The very recent advances of graphics processing unit (GPU) provide not only highly favorable performance for GPU enabled MD programs compared with CPU implementations but also an opportunity to manage with the computing power and memory demanding nature imposed on computer hardware by ReaxFF MD. In this paper, we present the algorithms of GMD-Reax, the first GPU enabled ReaxFF MD program with significantly improved performance surpassing CPU implementations on desktop workstations. The performance of GMD-Reax has been benchmarked on a PC equipped with a NVIDIA C2050 GPU for coal pyrolysis simulation systems with atoms ranging from 1378 to 27,283. GMD-Reax achieved speedups as high as 12 times faster than Duin et al.'s FORTRAN codes in Lammps on 8 CPU cores and 6 times faster than the Lammps' C codes based on PuReMD in terms of the simulation time per time-step averaged over 100 steps. GMD-Reax could be used as a new and efficient computational tool for exploiting very complex molecular reactions via ReaxFF MD simulation on desktop workstations.
Journal of molecular graphics & modelling 02/2013; 41C:1-11. · 2.17 Impact Factor
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Hao Zhou,
Minjia Yu,
Koichi Fukuda,
Jinteak Im,
Peng Yao,
Wei Cui,
Katarzyna Bulek,
Jarod Zepp,
Youzhong Wan,
Tae Whan Kim,
Weiguo Yin,
Victoria Ma,
James Thomas,
Jun Gu,
Jian-An Wang,
Paul E Dicorleto,
Paul L Fox,
Jun Qin, Xiaoxia Li
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ABSTRACT: Toll-like receptors transduce their signals through the adaptor molecule MyD88 and members of the IL-1R-associated kinase family (IRAK-1, 2, M and 4). IRAK-1 and IRAK-2, known to form Myddosomes with MyD88-IRAK-4, mediate TLR7-induced TAK1-dependent NFκB activation. IRAK-M was previously known to function as a negative regulator that prevents the dissociation of IRAKs from MyD88, thereby inhibiting downstream signalling. However, we now found that IRAK-M was also able to interact with MyD88-IRAK-4 to form IRAK-M Myddosome to mediate TLR7-induced MEKK3-dependent second wave NFκB activation, which is uncoupled from post-transcriptional regulation. As a result, the IRAK-M-dependent pathway only induced expression of genes that are not regulated at the post-transcriptional levels (including inhibitory molecules SOCS1, SHIP1, A20 and IκBα), exerting an overall inhibitory effect on inflammatory response. On the other hand, through interaction with IRAK-2, IRAK-M inhibited TLR7-mediated production of cytokines and chemokines at translational levels. Taken together, IRAK-M mediates TLR7-induced MEKK3-dependent second wave NFκB activation to produce inhibitory molecules as a negative feedback for the pathway, while exerting inhibitory effect on translational control of cytokines and chemokines.
The EMBO Journal 02/2013; · 9.20 Impact Factor
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ABSTRACT: IL-17 cytokines play a crucial role in a variety of inflammatory and autoimmune diseases. They signal through heterodimeric receptor complexes consisting of members of IL-17R family. A unique intracellular signaling domain was identified within all IL-17Rs, termed similar expression to fibroblast growth factor genes and IL-17R (SEFIR). SEFIR is also found in NF-κB activator 1 (Act1), an E3 ubiquitin ligase, and mediates its recruitment to IL-17Rs. In this study, to our knowledge, we report the structure of the first SEFIR domain from IL-17RB at 1.8Å resolution. SEFIR displays a five-stranded parallel β-sheet that is wrapped by six helices. Site-directed mutagenesis on IL-17RB identified helix αC as being critical for its interaction with Act1 and IL-25 (IL-17E) signaling. Using the current SEFIR structure as a template, the key functional residues in Act1 are also mapped as part of helix αC, which is conserved in IL-17RA and RC, suggesting this helix as a common structural signature for heterotypic SEFIR-SEFIR association. In contrast, helix αB' is important for homodimerization of Act1, implicating a dual ligand-binding model for SEFIR domain, with distinct structural motifs participating in either homotypic or heterotypic interactions. Furthermore, although the IL-17RB-SEFIR structure resembles closest to the Toll/IL-1R domain of TLR10 with low sequence homology, substantial differences were observed at helices αC, αD, and DD' loop. To our knowledge, this study provides the first structural view of the IL-17R intracellular signaling, unraveling the mechanism for the specificity of SEFIR versus Toll/IL-1R domain in their respective signaling pathways.
The Journal of Immunology 01/2013; · 5.79 Impact Factor
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Chenhui Wang,
Ling Wu,
Katarzyna Bulek,
Bradley N Martin,
Jarod A Zepp,
Zizhen Kang,
Caini Liu,
Tomasz Herjan,
Saurav Misra,
Julie A Carman,
Ji Gao,
Ashok Dongre,
Shujie Han,
Kevin D Bunting,
Jennifer S Ko,
Hui Xiao,
Vijay K Kuchroo,
Wenjun Ouyang, Xiaoxia Li
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ABSTRACT: Act1 is an essential adaptor in interleukin 17 (IL-17)-mediated signaling and is recruited to the receptor for IL-17 after stimulation with IL-17. Here we found that Act1 was a 'client' protein of the molecular chaperone hsp90. The D10N variant of Act1 (Act1(D10N)) that is linked to susceptibility to psoriasis was defective in its interaction with hsp90, which resulted in a global loss of Act1 function. Act1-deficient mice modeled the mechanistic link between loss of Act1 function and susceptibility to psoriasis. Although Act1 was necessary for IL-17-mediated inflammation, Act1-deficient mice had a hyperactive response of the T(H)17 subset of helper T cells and developed spontaneous IL-22-dependent skin inflammation. In the absence of IL-17 signaling, IL-22 was the main contributor to skin inflammation, which provides a molecular mechanism for the association of Act1(D10N) with psoriasis susceptibility.
Nature Immunology 12/2012; · 26.01 Impact Factor
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Muhammet F Gulen,
Katarzyna Bulek,
Hui Xiao,
Minjia Yu,
Ji Gao,
Lillian Sun,
Eleonore Beurel,
Oksana Kaidanovich-Beilin,
Paul L Fox,
Paul E Dicorleto,
Jian-An Wang,
Jun Qin,
David N Wald,
James R Woodgett,
Richard S Jope,
Julie Carman,
Ashok Dongre, Xiaoxia Li
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ABSTRACT: Interleukin-1 (IL-1)-induced activation of the mTOR kinase pathway has major influences on Th17 cell survival, proliferation, and effector function. Via biochemical and genetic approaches, the kinases IKKi and GSK3α were identified as the critical intermediate signaling components for IL-1-induced AKT activation, which in turn activated mTOR. Although insulin-induced AKT activation is known to phosphorylate and inactivate GSK3α and GSK3β, we found that GSK3α but not GSK3β formed a constitutive complex to phosphorylate and suppress AKT activation, showing that a reverse action from GSK to AKT can take place. Upon IL-1 stimulation, IKKi was activated to mediate GSK3α phosphorylation at S21, thereby inactivating GSK3α to promote IL-1-induced AKT-mTOR activation. Thus, IKKi has a critical role in Th17 cell maintenance and/or proliferation through the GSK-AKT-mTOR pathway, implicating the potential of IKKi as a therapeutic target.
Immunity 11/2012; · 21.64 Impact Factor
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ABSTRACT: Interleukin-1 (IL-1) receptor-associated kinase (IRAK1) is phosphorylated, ubiquitinated, and degraded upon IL-1 stimulation. IRAK1 can be ubiquitinated through both K48- and K63-linked polyubiquitin chains upon IL-1 stimulation. While the Pellino proteins have been shown to meditate K63-linked polyubiquitination on IRAK1, the E3 ligase for K48-linked ubiquitination of IRAK1 has not been identified. In this study, we report that the SCF (Skp1-Cullin1-F-box)-β-TrCP complex functions as the K48-linked ubiquitination E3 ligase for IRAK1. IL-1 stimulation induced the interaction of IRAK1 with Cullin1 and β-TrCP. Knockdown of β-TrCP1 and β-TrCP2 attenuated the K48-linked ubiquitination and degradation of IRAK1. Importantly, β-TrCP deficiency abolished the translocation TAK1-TRAF6 complex from the membrane to the cytosol, resulting in a diminishment of the IL-1-induced TAK1-dependent pathway. Taken together, these results implicate a positive role of β-TrCP-mediated IRAK1 degradation in IL-1-induced TAK1 activation.
Molecular and cellular biology 07/2012; 32(19):3990-4000. · 6.06 Impact Factor
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ABSTRACT: Cuprizone inhibits mitochondrial function and induces demyelination in the corpus callosum, which resembles pattern III lesions in multiple sclerosis patients. However, the molecular and cellular mechanism by which cuprizone induces demyelination remains unclear. Interleukin-17 (IL-17) secreted by T helper 17 cells and γδT cells are essential in the development of experimental autoimmune encephalomyelitis. In this study, we examined the importance of IL-17 signaling in cuprizone-induced demyelination. We found that mice deficient in IL-17A, IL-17 receptor C (IL-17RC), and adaptor protein Act1 (of IL-17R) all had reduced demyelination accompanied by lessened microglial and polydendrocyte cellular reactivity compared with that in wild-type mice in response to cuprizone feeding, demonstrating the essential role of IL-17-induced Act1-mediated signaling in cuprizone-induced demyelination. Importantly, specific deletion of Act1 in astrocytes reduced the severity of tissue injury in this model, indicating the critical role of CNS resident cells in the pathogenesis of cuprizone-induced demyelination. In cuprizone-fed mice, IL-17 was produced by CNS CD3(+) T cells, suggesting a source of IL-17 in CNS upon cuprizone treatment.
Journal of Neuroscience 06/2012; 32(24):8284-92. · 7.11 Impact Factor
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ABSTRACT: Interleukin 1 receptor-associated kinase 1(IRAK1), a key molecule in TLR/IL-1R-mediated signaling, is phosphorylated, ubiquitinated, and degraded upon ligand stimulation. We and others have recently identified Pellino proteins as novel RING E3 ubiquitin ligases involved in IRAK1 polyubiquitination and degradation. However, it remains unclear how each Pellino member distinctly regulates TLR/IL-1R signaling by modulating IRAK1 ubiquitination. In this study we examined the role of Pellino 2 in IL-1- and LPS-mediated signaling and gene expression by knocking down Pellino 2 in human 293-IL-1R cells and primary bone marrow macrophages. Pellino 2 (but not Pellino 1) knockdown abolished IL-1- and LPS-induced Lys-63-linked IRAK1 ubiquitination with reduced Lys-48-linked IRAK1 ubiquitination. Furthermore, Pellino 2 is required for TAK1-dependent NFκB activation. However, because of the retained TAK1-independent NFκB activation, the levels of IL-1- and LPS-induced NFκB activation were not substantially affected in Pellino 2 knockdown 293-IL-1R cells and primary macrophages, respectively. On the other hand, Pellino 2 knockdown reduced the IL-1- and LPS-induced inflammatory gene expression at late time points, which was accompanied by increased decay rates of the mRNAs of the inflammatory genes. Importantly, IL-1- and LPS-mediated JNK and ERK activation were substantially attenuated in Pellino 2 knock-down cells, implicating MAPK activation in TLR/IL-1R-induced mRNA stabilization. Taken together, this study demonstrated that Pellino 2 plays a critical role for TLR/IL-1R-mediated post-transcriptional control.
Journal of Biological Chemistry 06/2012; 287(30):25686-95. · 4.77 Impact Factor
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ABSTRACT: The effector T cell subset, Th17, plays a significant role in the pathogenesis of multiple sclerosis and of other autoimmune diseases. The signature cytokine, IL-17, engages the IL-17R and recruits the E3-ligase NF-κB activator 1 (Act1) upon stimulation. In this study, we examined the role of TNFR-associated factor (TRAF)4 in IL-17 signaling and Th17-mediated autoimmune encephalomyelitis. Primary cells from TRAF4-deficient mice displayed markedly enhanced IL-17-activated signaling pathways and induction of chemokine mRNA. Adoptive transfer of MOG35-55 specific wild-type Th17 cells into TRAF4-deficient recipient mice induced an earlier onset of disease. Mechanistically, we found that TRAF4 and TRAF6 used the same TRAF binding sites on Act1, allowing the competition of TRAF4 with TRAF6 for the interaction with Act1. Taken together, the results of this study reveal the necessity of a unique role of TRAF4 in restricting the effects of IL-17 signaling and Th17-mediated disease.
The Journal of Immunology 05/2012; 189(1):33-7. · 5.79 Impact Factor
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Zizhen Kang,
Shadi Swaidani,
Weiguo Yin,
Chenhui Wang,
Jillian L Barlow,
Muhammet Fatih Gulen,
Katarzyna Bulek,
Jeong-su Do,
Mark Aronica,
Andrew N J McKenzie,
Booki Min, Xiaoxia Li
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ABSTRACT: Interleukin-25 (IL-25 or IL-17E), a member of the structurally related IL-17 family, functions as an important mediator of T helper 2 cell-type (type 2) responses. We examined the cell type-specific role of IL-25-induced Act1-mediated signaling in protective immunity against helminth infection. Targeted Act1 deficiency in epithelial cells resulted in a marked delay in worm expulsion and abolished the expansion of the Lin(-)c-Kit(+) innate cell population in the mesenteric lymph node, lung, and liver. Th2 cell-inducing cytokine (IL-25 and IL-33) expression were reduced in the intestinal epithelial cells from the infected and IL-25-injected epithelial-specific Act1-deficient mice. Adoptive transfer of Lin(-)c-Kit(+) cells or combined injection of IL-25 and IL-33 restored the type 2 responses in these mice. Taken together, these results suggest that epithelial-specific Act1 mediates the expansion of the Lin(-)c-Kit(+) innate cell population through the positive-feedback loop of IL-25, initiating the type 2 immunity against helminth infection.
Immunity 05/2012; 36(5):821-33. · 21.64 Impact Factor
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ABSTRACT: Act1 is a negative regulator of B-cell activation factor of the TNF family (BAFF) and CD40L-induced signaling. BALB/C mice lacking Act1 develop systemic autoimmunity resembling systemic lupus erythematosus (SLE) and Sjögren's syndrome (SjS). SLE and SjS are characterized by anti-nuclear IgG autoantibody (ANA-IgG) production and inflammation of peripheral tissues. As autoantibody production can occur in a T-cell dependent or T-cell independent manner, we investigated the role of T-cell help during Act1-mediated autoimmunity. Act1-deficiency was bred onto C57Bl/6 (B6.Act1(-/-) ) mice and B6.TCRβ(-/-) TCRδ(-/-) Act1(-/-) (TKO) mice were generated. While TCRβ/δ-sufficient B6.Act1(-/-) mice developed splenomegaly and lymphadenopathy, hypergammaglobulinemia, elevated levels of ANA-IgG, and kidney pathology, TKO mice failed to develop any such signs of disease. Neither B6.Act1(-/-) nor TKO mice developed SjS-like disease, suggesting that epigenetic interactions on the BALB/C background are responsible for this phenotype in BALB/C.Act1(-/-) mice. Interestingly, BAFF-driven transitional B-cell abnormalities, previously reported in BALB/C.Act1(-/-) mice, were intact in B6.Act1(-/-) mice and largely independent of T cells. In conclusion, T cells are necessary for the development of SLE-like disease in B6.Act1(-/-) mice, but not BAFF-driven transitional B-cell differentiation.
European Journal of Immunology 05/2012; 42(7):1695-705. · 5.10 Impact Factor
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ABSTRACT: OBJECTIVE: Intestinal microflora and inflammatory cell infiltrates play critical roles in the pathogenesis of acute colitis. Ceruloplasmin is an acute-phase plasma protein produced by hepatocytes and activated macrophages, and has ferroxidase with bactericidal activities. The goal is to understand the role of ceruloplasmin in colitis progression in a genetically modified murine model. DESIGN: Experimental colitis was induced in ceruloplasmin null (Cp(-/-)) and wild-type (WT) mice by dextran sulphate sodium administration. The role of ceruloplasmin was further evaluated by transplantation of WT macrophages into Cp(-/-) mice. RESULTS: Cp(-/-) mice rapidly lost weight and were moribund by day 14, while WT mice survived at least 30 days. Colon culture supernatants from Cp(-/-) mice exhibited elevated levels of TNFα, KC and MCP-1, indicative of increased inflammation and neutrophil and macrophage infiltration. Elevated leucocytes and severe histopathology were observed in Cp(-/-) mice. Elevated protein carbonyl content was detected in colons from Cp(-/-) mice suggesting ceruloplasmin antioxidant activity might contribute to its protective function. Unexpectedly, intraperitoneal administration of human ceruloplasmin into Cp(-/-) mice did not afford protection. Bone marrow transplantation from WT mice or injection of isolated peripheral blood monocytes markedly reduced severity of colitis and morbidity in Cp(-/-) mice. CONCLUSION: Macrophage-derived ceruloplasmin contributes importantly to protection against inflammation and tissue injury in acute and chronic experimental colitis. The findings suggest that defects in ceruloplasmin expression or processing may influence the onset or progression of inflammatory bowel disease in patients.
Gut 02/2012; · 10.11 Impact Factor
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ABSTRACT: The maintenance of immune homeostasis requires the delicate balance between response to foreign antigens and tolerance to self. As such, when this balance is disrupted, immunodeficiency or autoimmunity may manifest. The adaptor molecule known as Act1 is a critical mediator of IL-17 receptor receptor family signaling. This chapter will detail the current understanding of Act1 's role in signal transduction as well as address the fundamental role of Act1 in autoimmunity. At the molecular level Act1 interacts with IL-17 R through the conserved SEFIR domain, binds TRAF proteins and exerts E3 ubiquitin ligase activity. In in vivo models, Act1 deficiency provides protection against experimental autoimmune diseases, such as colitis and EAE. Yet mice lacking in Act1 develop spontaneous autoimmune diseases. Indeed, the utility of Act1 seems to rely on the specific cell type expression that may determine the pathway that Act1 mediates.
Advances in experimental medicine and biology 01/2012; 946:223-35. · 1.09 Impact Factor
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ABSTRACT: mRNAs encoding inflammatory chemokines that recruit neutrophils frequently exhibit short half-lives that serve to limit their expression under inappropriate conditions but are often prolonged to ensure adequate levels during inflammatory response. Extracellular stimuli that modulate the stability of such mRNAs may be the same as the transcriptional activator, as is the case with TLR ligands, or may cooperate with independent transcriptional stimuli, as with IL-17, which extends the half-life of TNF-induced transcripts. These different stimuli engage independent signaling pathways that target different instability mechanisms distinguished by dependence on different regulatory nucleotide sequence motifs within the 3'UTRs, which involve that action of different mRNA-binding proteins. The selective use of these pathways by different stimuli and in distinct cell populations provides the potential for tailoring of chemokine expression patterns to meet specific needs in different pathophysiologic circumstances.
Journal of leukocyte biology 12/2011; 91(3):377-83. · 4.99 Impact Factor
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ABSTRACT: The cellular and molecular mechanisms driven by IL-25 and its cognate receptor IL-17RB necessary for the promotion of Th2-mediating pathogenic pulmonary inflammation remains to be defined. We have previously reported the critical role of the U-box-type E3 ubiquitin ligase Act1 (1) for the downstream signaling of the IL-17 cytokine family including the Th2-promoting cytokine IL-25 (IL-17E) (2). In this study, we report that IL-25-driven but not conventional IL-4-driven Th2 polarization and cytokine production is impaired in Act1-deficient T cells. Also, Act1 deficiency in the T cell compartment results in the abrogation of eosinophilic airway infiltration as well as airway hyperresponsiveness in mouse models of Ag-induced airway inflammation. The in vivo generation of Ag-specific Th2 cytokine-producing cells is defective in the absence of Act1 expression in T cells after OVA/aluminum hydroxide immunization. Notably, the production of OVA-specific IgG(1) but not IgG(2a) or IgE is also impaired. At the molecular level, we report that IL-25-mediated induction of Th2 master regulator GATA-3 and the transcription factor GFI-1 is attenuated in Act1-deficient T cells. Taken together, our findings indicate that Act1 expression in T cells is required for cellular and humoral Th2-mediated allergic responses and the development of airway hyperresponsiveness, in part, through Act1's function in IL-25-induced development of Th2 T cells.
The Journal of Immunology 08/2011; 187(6):3155-64. · 5.79 Impact Factor
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ABSTRACT: The pathophysiology of interstitial cystitis (IC) is unknown. Deficits in urothelial cell layers and autoimmune mechanisms may play a role.
To examine whether immunization of mice with recombinant mouse uroplakin II (rmUPK2), a bladder-specific protein, would provoke an autoimmune response sufficient to create an IC phenotype.
RmUPK2 complementary DNA was generated, transferred into a bacterial expression vector, and the generated protein was purified. Eight-week-old SWXJ female mice were immunized with rmUPK2 protein via subcutaneous injection of 200μg of rmUPK2 protein in 200μl of an emulsion.
Mice were euthanized 5 wk after immunization. Axillary and inguinal lymph node cells were tested for antigen-specific responsiveness and cytokine production, serum isotype antibody titers against rmUPK2 were determined, and gene expression of inflammatory mediators was measured in the bladder and other organs. For functional analysis, mice were placed in urodynamic chambers for 24-h micturition frequency and total voided urine measurements.
Immunization with rmUPK2 resulted in T-cell infiltration of the bladder urothelium and increased rmUPK2-specific serum antibody responses in the experimental autoimmune cystitis (EAC) mice models compared with controls. The ratio of bladder to body weight was increased in EAC mice. Quantitative reverse transcriptase polymerase chain reaction analysis showed elevated gene expression of tumor necrosis factor α, interferon γ, interleukin (IL)-17A, and IL-1β in bladder urothelium but not in other organs. Evaluation of 24-h micturition habits of EAC mice showed significantly increased urinary frequency (p<0.02) and significantly decreased urine output per void (p<0.021) when compared with control mice.
Our study showed that a bladder-specific autoimmune response sufficient to induce inflammation and EAC occurs in mice following immunization with rmUPK2. EAC mice displayed significant evidence of urinary frequency and decreased urine output per void. Further phenotype characterization of EAC mice should include evidence for pain and/or afferent hypersensitivity, and evidence of urothelial cell layer damage.
European urology 06/2011; 61(1):193-200. · 7.67 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is widely used to dissect molecular mechanisms of MS and to develop new therapeutic strategies. The T helper 17 (Th17) subset of CD4 T cells plays a crucial role in the development of EAE. IL-17, a cytokine produced by Th17 cells, participates in EAE pathogenesis through induction of inflammatory gene expression in target cells. Recent work has shown that Act1, a U-box E3 ubiquitin ligase, is recruited to IL-17 receptor (IL-17R) upon IL-17 stimulation and is required for IL-17-mediated signaling. Here, we review the molecular and cellular mechanisms by which IL-17 and Act1-mediated signaling contribute to EAE.
Trends in Immunology 05/2011; 32(5):232-9. · 10.40 Impact Factor
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Tae Whan Kim,
Maria Febbraio,
Peggy Robinet,
Brandon Dugar,
Diane Greene,
Anna Cerny,
Eicke Latz,
Raymond Gilmour,
Kirk Staschke,
Guy Chisolm,
Paul L Fox,
Paul E DiCorleto,
Jonathan D Smith, Xiaoxia Li
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ABSTRACT: Exciting discoveries related to IL-1R/TLR signaling in the development of atherosclerosis plaque have triggered intense interest in the molecular mechanisms by which innate immune signaling modulates the onset and development of atherosclerosis. Previous studies have clearly shown the definitive role of proinflammatory cytokine IL-1 in the development of atherosclerosis. Recent studies have provided direct evidence supporting a link between innate immunity and atherogenesis. Although it is still controversial about whether infectious pathogens contribute to cardiovascular diseases, direct genetic evidence indicates the importance of IL-1R/TLR signaling in atherogenesis. In this study, we examined the role of IL-1R-associated kinase 4 (IRAK4) kinase activity in modified low-density lipoprotein (LDL)-mediated signaling using bone marrow-derived macrophage as well as an in vivo model of atherosclerosis. First, we found that the IRAK4 kinase activity was required for modified LDL-induced NF-κB activation and expression of a subset of proinflammatory genes but not for the activation of MAPKs in bone marrow-derived macrophage. IRAK4 kinase-inactive knockin (IRAK4KI) mice were bred onto ApoE(-/-) mice to generate IRAK4KI/ApoE(-/-) mice. Importantly, the aortic sinus lesion formation was impaired in IRAK4KI/ApoE(-/-) mice compared with that in ApoE(-/-) mice. Furthermore, proinflammatory cytokine production was reduced in the aortic sinus region of IRAK4KI/ApoE(-/-) mice compared with that in ApoE(-/-) mice. Taken together, our results indicate that the IRAK4 kinase plays an important role in modified LDL-mediated signaling and the development of atherosclerosis, suggesting that pharmacological inhibition of IRAK4 kinase activity might be a feasible approach in the development of antiatherosclerosis drugs.
The Journal of Immunology 03/2011; 186(5):2871-80. · 5.79 Impact Factor
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Youzhong Wan,
Tae Whan Kim,
Minjia Yu,
Hao Zhou,
Michifumi Yamashita,
Zizhen Kang,
Weiguo Yin,
Jian-An Wang,
James Thomas,
Ganes C Sen,
George R Stark, Xiaoxia Li
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ABSTRACT: Bone marrow-derived plasmacytoid dendritic cells (pDCs) from IL-1R-associated kinase (IRAK)2-deficient mice produced more IFNs than did wild-type pDCs upon stimulation with the TLR9 ligand CpG. Furthermore, in CpG-stimulated IRAK2-deficient pDCs there was increased nuclear translocation of IFN regulatory factor 7, the key transcription factor for IFN gene transcription in these cells. In IRAK2-deficient macrophages, enhanced NF-κB activation and increased expression of CpG-induced genes were detected within 2 h after treatment. However, at later times, NF-κB activation was decreased and, in contrast to the results with IFN, there was less secretion of other proinflammatory cytokines (such as TNF-α) and chemokines in CpG-stimulated IRAK2-deficient pDCs and macrophages. Therefore, although IRAK2 is a negative regulator of TLR9-mediated IFN production through its modulation of the transcriptional activity of IFN regulatory factor 7, it is also a positive regulator of TLR9-mediated proinflammatory cytokine and chemokine production at some level subsequent to transcription.
The Journal of Immunology 03/2011; 186(5):3006-14. · 5.79 Impact Factor
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ABSTRACT: Interleukin-1 receptor-associated kinase 2 (IRAK2) has been shown to be essential for lipopolysaccharide (LPS)-mediated posttranscriptional control of cytokine and chemokine production. In this study, we investigated the role of IRAK2 kinase activity in LPS-mediated posttranscriptional control by reconstituting IRAK2-deficient macrophages with either wild-type or kinase-inactive IRAK2. Compared with wild-type IRAK2 (IRAK2-WT) macrophages, kinase-inactive IRAK2 (IRAK2-KD) macrophages show reduced cytokine and chemokine mRNA stability and translation in response to LPS. Further, LPS-treated IRAK2-KD macrophages also show reduced activation of MKK3/6, MNK1, and eIF4E and attenuated toll-like receptor 4-induced tristetraprolin modification and stabilization. Taken together, these results suggest that the kinase activity of IRAK2 is required for the optimal activation of mitogen-activated protein kinase signaling, which regulates cytokine and chemokine production at posttranscriptional levels.
Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 02/2011; 31(5):415-22. · 1.63 Impact Factor
